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Network‐regulated organ allometry: The developmental regulation of morphological scaling
Abstract
Morphological scaling relationships, or allometries, describe how traits grow coordinately and covary among individuals in a population. The developmental regulation of scaling is essential to generate correctly proportioned adults across a range of body sizes, while the mis‐regulation of scaling may result in congenital birth defects. Research over several decades has identified the developmental mechanisms that regulate the size of individual traits. Nevertheless, we still have poor understanding of how these mechanisms work together to generate correlated size variation among traits in response to environmental and genetic variation. Conceptually, morphological scaling can be generated by size‐regulatory factors that act directly on multiple growing traits (trait‐autonomous scaling), or indirectly via hormones produced by central endocrine organs (systemically regulated scaling), and there are a number of well‐established examples of such mechanisms. There is much less evidence, however, that genetic and environmental variation actually acts on these mechanisms to generate morphological scaling in natural populations. More recent studies indicate that growing organs can themselves regulate the growth of other organs in the body. This suggests that covariation in trait size can be generated by network‐regulated scaling mechanisms that respond to changes in the growth of individual traits. Testing this hypothesis, and one of the main challenges of understanding morphological scaling, requires connecting mechanisms elucidated in the laboratory with patterns of scaling observed in the natural world.
This article is categorized under:
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing
Comparative Development and Evolution > Organ System Comparisons Between Species
... Although previous work in bees has focused on how elevated developmental temperatures affect specific morphological traits, such as wings and tongue length, it remains unclear how different body parts are affected. As organs vary in their sensitivity to temperature during genesis (Vea and Shingleton, 2020), exposure to elevated temperatures during development is likely to have varying effects on different body parts. Allometrydefined here as how the size of a morphological trait scales with body sizeis a way to explore whether and how organ genesis differs with variations in developmental temperature. ...
... The resulting trade-offs generate diversity in the ratio between their size and body size (Agrawal, 2020). Temperature deviations during development can affect this investment (Vea and Shingleton, 2020). For example, in Drosophila melanogaster, the cell proliferation of the wing imaginal discs is less sensitive to developmental temperature than the cell proliferation of the leg imaginal disc, leading to different growth rates of different morphological traits under different developmental temperatures (McDonald et al., 2018). ...
The impact of global warming on wild bee decline threatens the pollination services they provide. Exposure to temperatures above optimal during development is known to reduce adult body size but how it affects the development and scaling of body parts remains unclear. In bees, a reduction in body size and/or a reduction in body parts, such as the antennae, tongue and wings, and how they scale with body size (i.e. their allometry) could severely affect their fitness. To date, it remains unclear if and how temperature affects body size and the scaling of morphological traits in bees. To address this knowledge gap, we exposed both males and workers of Bombus terrestris to elevated temperature during development and assessed the effects on (i) the size of morphological traits and (ii) the allometry between these traits. Colonies were exposed to optimal (25°C) or stressful (33°C) temperatures. We then measured the body size, wing size, antenna and tongue length, as well as the allometry between these traits. We found that workers were smaller and the antennae of both castes were reduced at the higher temperature. However, tongue length and wing size were not affected by developmental temperature. The allometric scaling of the tongue was also affected by developmental temperature. Smaller body size and antennae could impair both individual and colony fitness, by affecting foraging efficiency and, consequently, colony development. Our results encourage further exploration of how the temperature-induced changes in morphology affect functional traits and pollination efficiency.
... Despite body size being the focus of many studies, as well as a trait that is easy to measure and widely available in the literature, establishing general patterns of size evolution is challenging (Clarke 2021). Body size is a complex trait, not only because there are many selective pressures underlying its variation in nature but also because it encompasses different dimensions and thus the potential to be measured by distinct variables (Vea and Shingleton 2020). The multidimensional aspect of body size opens several possibilities by which organisms can change their size, and by altering body proportions (e.g. ...
... As body size reflects the collective size of the body's component parts (Vea and Shingleton 2020), there are multiple evolutionary paths by which fishes and, organisms in general, can change their body size. We therefore investigate the evolution of three body size components (length, depth and width) and two composite metrics (body mass and the geometric mean of length, depth and width, sensu Price et al. 2019) within 42 orders of teleosts. ...
Body size influences nearly every aspect of an organism’s biology and ecology. When studying body size, researchers often focus on a single dimension, such as length, despite the fact that size can evolve by altering multiple body dimensions. The distinct ways organisms change their size can have profound consequences on evolutionary and ecological processes. Here, we investigate the evolution of size as a complex trait by exploring the interaction between body length, depth, and width across 42 orders of teleost fishes. Using Ornstein-Uhlenbeck models, we compare shifts in the adaptive landscapes of each of the three size components, and in the scaling relationships between them. We find that fishes change their size in a myriad of ways: changes in length, depth and width rarely co-occur on the phylogeny or in accordance with composite measures of size (body mass or the geometric mean). Body size diversity tends to accumulate along trajectories close to isometry but there is also some variation in the allometric regimes. Finally, orders with scaling shifts are more species rich than those without shifts, suggesting that body size diversity trajectories have the potential to be associated with distinct diversification scenarios in teleosts. Based on the evolutionary relationships we found between size components, we recommend that researchers treat body size as a complex trait to properly evaluate the patterns and processes of size variation in nature.
... Obviously, developmental tempo and organ size are two closely interrelated variables during individual growth (i.e. embryonic development and postnatal growth) and morphogenesis, both of which must be tightly harmonized to ensure the correct establishment of body plan and therefore are the result of a precisely controlled process (Vea and Shingleton, 2021). ...
... The mechanisms that regulate organ size have been well investigated in nonmammalian models, particularly in Drosophila melanogaster, in which roles of TOR (target of rapamycin), insulin/IGF (insulin-like growth factor), Ras/Raf/MAPK, JNK (c-Jun N-terminal kinase), and Hippo signaling pathways are well defined (Gokhale and Shingleton, 2015;Vea and Shingleton, 2021). In mammals, Hippo and IGF pathways have been evidenced to be involved in controlling organ size (Zaina and Squire, 1998;Tumaneng et al., 2012;Barry et al., 2013;Liu et al., 2014;Yu et al., 2015;Zhang et al., 2017). ...
The developing human and mouse teeth constitute an ideal model system to study the regulatory mechanism underlying organ growth control since their teeth share highly conserved and well-characterized developmental processes and their developmental tempo varies notably. In the current study, we manipulated heterogenous recombination between human and mouse dental tissues and demonstrate that the dental mesenchyme dominates the tooth developmental tempo and FGF8 could be a critical player during this developmental process. Forced activation of FGF8 signaling in the dental mesenchyme of mice promoted cell proliferation, prevented cell apoptosis via p38 and perhaps PI3K-Akt intracellular signaling, and impelled the transition of the cell cycle from G1- to S-phase in the tooth germ, resulting in the slowdown of the tooth developmental pace. Our results provide compelling evidence that extrinsic signals can profoundly affect tooth developmental tempo and the dental mesenchymal FGF8 could be a pivotal factor in controlling the developmental pace in a non-cell-autonomous manner during mammalian odontogenesis.
... Frontiers in Cell and Developmental Biology frontiersin.org 03 size was not adjusted for body size as scaling relationship between organs typically occurs during ontogenetic growth (Vea and Shingleton, 2021). In comparative biology, recent studies have also questioned traditional methods for body-size adjustment as they i) do not adequately separate the effects of body size from those of other biological and ecological factors on a specific phenotypic trait (Glazier, 2022) and ii) can spuriously change the sign of regression coefficients compared to the original values, which could lead to inferential biases in biological studies (Rogell et al., 2019). ...
Background: In polygynous species, the development of secondary sexual characters is usually decisive for male reproductive success. However, our understanding about the links between the growth of these traits and reproductive efficiency is still elusive. Most research efforts in this topic have been also focused on adult males, although the development of some secondary sexual characters, like bovid horns, typically starts after birth, continues during the puberty and in some species, such as the common eland, slows or even stops during adulthood. In this study, we investigated the relationships between horn size and testicular function during sexual development in common elands using a comprehensive approach that considers both spermatogenic and sperm parameters.
Methods: Twenty-two non-sexually mature common elands were used for the present study. Horn size, body mass, testes mass, and gonadosomatic index were assessed. Spermatogenic activity was determined by cytological and histological analyses. Sperm concentration, morphology, morphometry, and intramale variation in sperm size were evaluated on epididymal sperm samples. Cluster analysis was performed to explore the influence of age on relationships between horn size and reproductive function.
Results: We found that bigger horns are associated with increased Sertoli cell efficiency and reduced intramale variation in sperm size. Both parameters were not related to one another while they have shown to be associated with enhanced sperm quality in ungulates. Moreover, horn size was positively linked to the testis mass, sperm concentration, and testicular investment in the seminiferous epithelium. Spiral length and basal circumference were the horn traits most strongly correlated with spermatogenic and sperm parameters as well as those responsible for the sexual dimorphism in this species. Cluster analysis rendered two groups: the first one including males ≤30 months old, while the second one those >30 months old. Horn development and reproductive function were still correlated within age groups, with the strongest relationship found between horn size and sperm size homogeneity in males >30 months old.
Conclusion: Taken together, our results indicate that horn size can be regarded as a good index of male reproductive potential during sexual development and provide insights into the role of secondary sexual characters in sexual selection dynamics.
... At the scale of organs, size proportions follow robust allometric relations 13,14 , and proportions of body parts usually scale appropriately over a wide range of body sizes 15 . Combined experimental and theoretical work provides elegant explanations for how tissue patterning appropriately scales with tissue size during development 16,17 . ...
Even slight imbalance between the growth rate of different organs can accumulate to a large deviation from their appropriate size during development. Here, we use live imaging of the pharynx of C. elegans to ask if and how organ size scaling nevertheless remains uniform among individuals. Growth trajectories of hundreds of individuals reveal that pharynxes grow by a near constant volume per larval stage that is independent of their initial size, such that undersized pharynxes catch-up in size during development. Tissue-specific depletion of RAGA-1, an activator of mTOR and growth, shows that maintaining correct pharynx-to-body size proportions involves a bi-directional coupling between pharynx size and body growth. In simulations, this coupling cannot be explained by limitation of food uptake alone, and genetic experiments reveal an involvement of the mechanotransducing transcriptional co-regulator yap-1. Our data suggests that mechanotransduction coordinates pharynx growth with other tissues, ensuring body plan uniformity among individuals.
... [86][87][88] Numerous artificial selection experiments have altered the slope of a static trait allometry (e.g., wing size in Drosophila melanogaster 89,90 and the butterfly Bicyclus anynana 91 and eyestalk length in the fly Cyrtodiopsis dalmanni 92 ), and developmental genetic studies now point toward candidate genes and physiological pathways that could contribute to static allometry slope evolution. [93][94][95][96][97][98][99][100][101][102] Yet it is also clear that changing a static allometry slope is not easy-responses to selection are erratic and much slower than responses to selection applied to the intercept of these same allometries. 89,90 Indeed, a meta-analysis of more than 300 empirical studies of static trait allometry evolution concluded that allometry slopes likely change slowly over long timescales (>1 million years) in contrast with allometry intercepts, which routinely differ among local populations. ...
... Although body size is perhaps the most apparent trait of any organism, it is far from being a simple one. At the ontogenetic level, the pathways leading to adult body sizes are inevitably intricate (Stern & Emlen, 1999;Day & Lawrence, 2000;Vea & Shingleton, 2021). At the ecological and evolutionary levels, the multitude of ways in which body size interacts with the environment make it challenging to understand how this trait evolves (Blanckenhorn, 2000;Kingsolver & Huey, 2008;Chown & Gaston, 2010). ...
Dry body mass (DBM) is perhaps the most biologically informative variable describing body size in invertebrates. Unfortunately, obtaining species-specific indices of DBM is problematic because body mass inevitably changes during the course of the life of an individual. Here, we present a phylogenetically informed analysis of allometric relationships between body size and various linear measurements in the moth family Geometridae, which relies on DBM recorded at a fixed time point of adult life. We demonstrate that all measurements of wing size predict DBM with reasonable accuracy, with the distance between the most distal ends of the two forewings in traditionally mounted moths showing the best performance. Abdomen width provides independent morphometric information and can be used as a proxy of body plan, i.e. a measurement of shape that is not dependent on size. Incorporating abdomen width into the regression models considerably increases their predictive ability. We also show that the allometric relationships are reasonably consistent between the two sexes, between monophyletic clades of Geometridae and between the two geographical regions involved in the study (northern Europe and equatorial Africa). The derived equations thus appear to be general enough to be applied in various studies, from comparative phylogenetic analyses to applied projects monitoring insect biomass.
... To test this hypothesis, we investigate whether pathways related to protein synthesis, cell proliferation and growth, namely the insulin/mTOR signalling pathway, are upregulated in the pronotum and wings [8]. The insulin/mTOR signalling pathway has been well studied in insect systems and plays a major role in the regulation of organ size by controlling growth rate and duration [9][10][11]. Insulin is key for the coordination of whole-body growth such that the appropriate proportions of organs and appendages with overall body size are achieved [12,13]. ...
Treehoppers of the insect family Membracidae have evolved enlarged and elaborate pronotal structures, which is hypothesized to involve co-opted expression of genes that are shared with the wings. Here, we investigate the similarity between the pronotum and wings in relation to growth. Our study reveals that the ontogenetic allometry of the pronotum is similar to that of wings in Membracidae, but not the outgroup. Using transcriptomics, we identify genes related to translation and protein synthesis, which are mutually upregulated. These genes are implicated in the eIF2, eIF4/p70S6K and mTOR pathways, and have known roles in regulating cell growth and proliferation. We find that species-specific differential growth patterning of the pronotum begins as early as the third instar, which suggests that expression of appendage patterning genes occurs long before the metamorphic molt. We propose that a network related to growth and size determination is the more likely mechanism shared with wings. However, regulators upstream of the shared genes in pronotum and wings need to be elucidated to substantiate whether co-option has occurred. Finally, we believe it will be helpful to distinguish the mechanisms leading to pronotal size from those regulating pronotal shape as we make sense of this spectacular evolutionary innovation.
... In multicellular organisms, the size of each organ grows proportional to other organs and to the entire body. This morphological scaling relationship is known as allometry (Frankino et al., 2019;Vea and Shingleton, 2020). Understanding how allometry arises is a fundamental question in biology. ...
The size of an organ is proportional to the other body parts or the whole body. This relationship is known as allometry. Understanding how allometry is determined is a fundamental question in biology. Here we tested the hypothesis that local insulin-like growth factor (Igf) signaling is critical in regulating organ size and its allometric scaling by organ-specific expression of Igf binding proteins (Igfbp). Overexpression of Igfbp2a or 5b in the developing zebrafish eye, heart, and inner ear resulted in a disproportional reduction in their growth relative to the body. Stable transgenic zebrafish with lens-specific Igfbp5b expression selectively reduced adult eye size. The action is Igf-dependent because an Igf-binding deficient Igfbp5b mutant had no effect. Targeted expression of a dominant-negative Igf1 receptor (dnIgf1r) in the lens caused a similar reduction in relative eye growth. Furthermore, co-expression of IGF-1 with an Igfbp restored the eye size. Finally, co-expression of a constitutively active form of Akt with Igfbp or dnIgf1r restored the relative eye growth. These data suggest that local Igf availability and Igf signaling activity are critical determinants of organ size and allometric scaling in zebrafish.
... An organism is capable of buffering developmental pathways against genetic or environmental perturbations (Kitano 2004;Masel and Siegal 2009;Mestek and Barkoulas 2016;Wilkins 1997) to maintain developmental stability and make sure the precision of developmental progression, in order to produce an ''ideal'' form regardless of different circumstances (Auffray et al. 1999;Palmer 1994;Van Dongen and Lens 2000). Once the equilibrium is broken, deviation from the developmental trajectory due to mis-regulation of allometry might be lethal (Vea and Shingleton 2020) and needs to be prevented as best as possible. The ability to maintain developmental stability is therefore regarded as a premise for plants surviving different stressful environments (Elgart et al. 2015). ...
How plants respond to density via modular plasticity is obscure, probably because relevant studies using covariance analysis (ANCOVA) and allometric analysis rarely focus on multiple stages of plant growth, and also the two approaches are seldom used simultaneously. In this study, a field experiment evaluated the effects of three density levels on resource allocation traits in Abutilon theophrasti and tested the degree to which these were explained by indirect effects of density on biomass over time. Results showed inconsistent responses in allocation traits and allometric relationships at each growth stage. At 30 days of plant growth, high density increased root/stem, root/leaf, and stem/leaf, but did not affect any allometric relationships. At 50 days, density altered most mass and ratio traits, but not for allometric exponents. At 70 days, density altered allometric relationships, but did not affect plant allocation patterns. The stage-dependent allometric relationships and the fact that allocation plasticity and allometric plasticity did not coincide both suggested that one-stage allometric plasticity might be apparent plasticity. In response to the increase of density, plants first altered the strategy of biomass partitioning and then growth rate or developmental stage, indicating that density effects intensified over time. For plasticity in a modular trait, size effects can be regarded as a component of (indirect) environmental effects, with the residual variation after removal of size effects being the other component of plant (direct) active response. The insights into apparent plasticity of allometry and two components of plasticity should be of essential importance to investigating phenotypic plasticity and its ecological and evolutionary implications.
... A number of recent studies support the hypothesis that SSD in Drosophila is generated by the same developmental-genetic mechanisms that regulate nutritional plasticity of body size; specifically the insulin/IGF-signalling (IIS) and TOR-signalling pathways (see [30][31][32]. The IIS responds to circulating insulin-like peptides (dILPS in Drosophila), which are released in a nutrient-dependent manner and bind to the insulin receptors (InR) of dividing cells [33]. Binding activates a signaltransduction pathway that ultimately controls the expression of genes involved in regulating cell survival, growth, and proliferation [34]. ...
The difference in body size between females and males, or sexual size dimorphism (SSD), is almost ubiquitous, and yet we have a remarkably poor understanding of the developmental-genetic mechanisms that generate it. Such an understanding is important if we are to distinguish between the many theoretical models of SSD evolution. One such model is the condition dependence hypothesis, which proposes that the body size of the larger sex is also more environmentally sensitive, a phenomenon called sex-specific plasticity (SSP). Because SSP generates differences in female and male body size, selection on plasticity may underlie the evolution of sexual size dimorphism. To test this hypothesis, however, we need to know the genetic architecture of both SSD and SSP, which is challenging because both are characteristics of populations not individuals. Here, we overcome this challenge by using isogenic lineages of Drosophila to measure both SSD and SSP for a genotype. We demonstrate extensive genetic variation for SSD among genotypes that is tightly correlated with variation in SSP, indicating that the same developmental-genetic mechanisms regulate both phenomena. These data support the condition dependence hypothesis and suggest that the observed SSD is a consequence of selection on the developmental-genetic mechanisms that regulate SSP.
... The allometry of development has long been of interest to developmental physiologists (Gould, 1975;Weder and Schork, 1994;Stern and Emlen, 1999;Singer and Mühlfeld, 2007;Vea and Shingleton, 2021). However, a fundamental challenge that remains unresolved involves reconciling two basic yet conflicting tenets of allometry and development (Burggren, 2020b). ...
... There is also no overlap between the genes that control abdominal or thorax size or the temperature-associated variation therein and the genes that we detect as candidate genes impacting animal weight. This finding links to studies from the field of allometry in a variety of animals that demonstrate that body parts do not necessarily scale equally with overall body size, thus leading to different proportions of body parts to each other 76,77 . If the various body parts then have different densities, which is the case for muscle versus body fat, the body weight does not simply reflect size. ...
Body size and weight show considerable variation both within and between species. This variation is controlled in part by genetics, but also strongly influenced by environmental factors including diet and the level of activity experienced by the individual. Due to the increasing obesity epidemic in much of the world, there is considerable interest in the genetic factors that control body weight and how weight changes in response to exercise treatments. Here, we address this question in the Drosophila model system, utilizing 38 strains of the Drosophila Genetics Reference Panel. We use GWAS to identify the molecular pathways that control weight and weight changes in response to exercise. We find that there is a complex set of molecular pathways controlling weight, with many genes linked to the central nervous system (CNS). The CNS also plays a role in the weight change with exercise, in particular, signaling from the CNS. Additional analyses revealed that weight in Drosophila is driven by two factors, animal size, and body composition, as the amount of fat mass versus lean mass impacts the density. Thus, while the CNS appears to be important for weight and exercise-induced weight change, signaling pathways are particularly important for determining how exercise impacts weight.
... An organism is capable to buffer developmental pathways against genetic or environmental perturbations (Kitano 2004;Masel & Siegal 2009;Mestek Boukhibar & Barkoulas 2016;Wilkins 1997), to maintain developmental stability and make sure the precision of developmental progression, in order to produce an "ideal" form regardless of different circumstances (Auffray et al. 1999;Palmer 1994;Van Dongen & Lens 2000). Once the equilibrium is broken, deviation from developmental trajectory due to mis-regulation of allometry might be lethal (Vea & Shingleton 2020) and prevented as best as possible. The ability to maintain developmental stability is thereby regarded as a premise for plants surviving different stressful environments (Elgart et al. 2015). ...
How plants respond to density via modular plasticity is obscure, probably because relevant studies using covariance and allometry analyses rarely focus on multiple stages of plant growth, and also the two approaches are seldom used simultaneously in a same study. To address this issue, a field experiment was conducted by subjecting plants of Abutilon theophrasti to low, medium and high densities and measuring the mass of various plant modules, before covariance and allometry analyses at three stages of plant growth. Results showed inconsistent responses in allocation traits and allometric relationships at each growth stage. At 30 d, high density increased root:stem, root:leaf and stem:leaf ratios, but did not affect any allometric relationships. At 50 d, density altered most allocation traits, but not for allometric exponents. At 70 d, density altered allometric relationships, with no effects on allocation traits. The stage-dependent allometric relationships and inconsistent results of allometric and covariance analyses suggested one-stage allometric plasticity might be apparent plasticity. In response to the increase of density, plants first altered the strategy of biomass partitioning, then growth rate or developmental stage, indicating density effects intensified over time. For plasticity in a modular trait, size effects can be regarded as a component of (indirect) environmental effects, with the left variation after removal of size effects being the other component of plant (direct) active response. The insights into apparent plasticity of allometry and two components of plasticity should be of essential importance to investigating phenotypic plasticity and its implications in plants.
The magnitude of many kinds of biological structures and processes scale with organismal size, often in regular ways that can be described by power functions. Traditionally, many of these “biological scaling” relationships have been explained based on internal geometric, physical, and energetic constraints according to universal natural laws, such as the “surface law” and “3/4‐power law”. However, during the last three decades it has become increasingly apparent that biological scaling relationships vary greatly in response to various external (environmental) factors. In this review, I propose and provide several lines of evidence supporting a new ecological perspective that I call the “mortality theory of ecology” (MorTE). According to this viewpoint, mortality imposes time limits on the growth, development, and reproduction of organisms. Accordingly, small, vulnerable organisms subject to high mortality due to predation and other environmental hazards have evolved faster, shorter lives than larger, more protected organisms. A MorTE also includes various corollary, size‐related internal and external causative factors (e.g. intraspecific resource competition, geometric surface area to volume effects on resource supply/transport and the protection of internal tissues from environmental hazards, internal homeostatic regulatory systems, incidence of pathogens and parasites, etc.) that impact the scaling of life. A mortality‐centred approach successfully predicts the ranges of body‐mass scaling slopes observed for many kinds of biological and ecological traits. Furthermore, I argue that mortality rate should be considered the ultimate (evolutionary) driver of the scaling of life, that is expressed in the context of other proximate (functional) drivers such as information‐based biological regulation and spatial (geometric) and energetic (metabolic) constraints.
Morphological scaling relationships between the sizes of individual traits and the body captures the characteristic shape of a species, and their evolution is the primary mechanism of morphological diversification. However, we have almost no knowledge of the genetic variation of scaling, which is critical if we are to understand how scaling evolves. Here we explore the genetics of population scaling relationships (scaling relationships fit to multiple genetically-distinct individuals in a population) by describing the distribution of individual scaling relationships (genotype-specific scaling relationships that are unseen or cryptic). These individual scaling relationships harbor the genetic variation in the developmental mechanisms that regulate trait growth relative to body growth, and theoretical studies suggest that their distribution dictates how the population scaling relationship will respond to selection. Using variation in nutrition to generate size variation within 197 isogenic lineages of Drosophila melanogaster, we reveal extensive variation in the slopes of the wing-body and leg-body individual scaling relationships among genotypes. This variation reflects variation in the nutritionally-induced size plasticity of the wing, leg, and body. Surprisingly, we find that variation in the slope of individual scaling relationships primarily results from variation in nutritionally-induced plasticity of body size, not leg or wing size. These data allow us to predict how different selection regimes affect scaling in Drosophila, and is the first step in identifying the genetic targets of such selection. More generally, our approach provides a framework for understanding the genetic variation of scaling, an important prerequisite to explaining how selection changes scaling and morphology.
Rhinoceros beetle ( Trypoxylus dichotomus ) males have pitchfork-shaped head horns, which they use to pry rival males from the trunks of trees. In the largest males these horns can be three times the length of horns in the two closest sister species. Because this weapon functions as a lever, longer horns should lift with less force than shorter horns (the "paradox of the weakening combatant") unless other elements of the weapon system (e.g., input lever length, muscle mass) evolve to compensate. We used next-generation sequencing approaches to consolidate 23 sample locations into 8 genetically distinguishable populations, reconstructing their historical relationships and providing a comprehensive picture of the evolution of this horn lever system. We show that head horns likely increased in length independently in the Northern and Southern lineages. In both instances this resulted in weaker lifting forces, but this mechanical disadvantage was later ameliorated, to some extent and in some locations, by subsequent reductions to horn length, changes in muscle size, or by an increase in input lever length (head height). Our results reveal an exciting geographic mosaic of differences in weapon size, weapon force, and in the extent and nature of mechanical compensation. Reconstructing the evolution of this weapon system offers critical insights towards meaningfully linking mating system dynamics, selection patterns, and diversity in sexually selected traits.
Adult females and males of most species differ in many aspects of their morphology, physiology and behavior, in response to sex-specific selective pressures that maximize fitness. While we have an increasingly good understanding of the genetic mechanisms that initiate these differences, the sex-specific developmental trajectories that generate them are much less well understood. Here we review recent advances in the sex-specific regulation of development focusing on two models where this development is increasingly well understood: Sexual dimorphism of body size in the fruit fly Drosophila melanogaster and sexual dimorphism of horns in the horned beetle Onthophagus taurus. Because growth and development are also supported by metabolism, the regulation of sex-specific metabolism during and after development is an important aspect of the generation of female and male phenotypes. Hitherto, the study of sex-specific development has largely been independent of the study of sex-specific metabolism. Nevertheless, as we discuss in this review, recent research has begun to reveal considerable overlap in the cellular and physiological mechanisms that regulate sex-specific development and metabolism.
The insulin/IGF-signaling pathway is central in control of nutrient-dependent growth during development, and in adult physiology and longevity. Eight insulin-like peptides (DILP1–8) have been identified in Drosophila, and several of these are known to regulate growth, metabolism, reproduction, stress responses, and lifespan. However, the functional role of DILP1 is far from understood. Previous work has shown that dilp1/DILP1 is transiently expressed mainly during the pupal stage and the first days of adult life. Here, we study the role of dilp1 in the pupa, as well as in the first week of adult life, and make some comparisons to dilp6 that displays a similar pupal expression profile, but is expressed in fat body rather than brain neurosecretory cells. We show that mutation of dilp1 diminishes organismal weight during pupal development, whereas overexpression increases it, similar to dilp6 manipulations. No growth effects of dilp1 or dilp6 manipulations were detected during larval development. We next show that dilp1 and dilp6 increase metabolic rate in the late pupa and promote lipids as the primary source of catabolic energy. Effects of dilp1 manipulations can also be seen in the adult fly. In newly eclosed female flies, survival during starvation is strongly diminished in dilp1 mutants, but not in dilp2 and dilp1/dilp2 mutants, whereas in older flies, only the double mutants display reduced starvation resistance. Starvation resistance is not affected in male dilp1 mutant flies, suggesting a sex dimorphism in dilp1 function. Overexpression of dilp1 also decreases survival during starvation in female flies and increases egg laying and decreases egg to pupal viability. In conclusion, dilp1 and dilp6 overexpression promotes metabolism and growth of adult tissues during the pupal stage, likely by utilization of stored lipids. Some of the effects of the dilp1 manipulations may carry over from the pupa to affect physiology in young adults, but our data also suggest that dilp1 signaling is important in metabolism and stress resistance in the adult stage.
Morphological diversity is dominated by variation in body proportion [1], which can be described with scaling relationships and mathematical equations, following the pioneering work of D'Arcy Thompson [2] and Julian Huxley [3]. Yet, the cellular processes underlying divergence in size and shape of morphological traits between species remain largely unknown [4-8]. Here, we compare the ovipositors of two related species, Drosophila melanogaster and D. suzukii. D. suzukii has switched its egg-laying niche from rotting to ripe fruit [9]. Along with this shift, the D. suzukii ovipositor has undergone a significant change in size and shape [10]. Using an allometric approach, we find that, while adult ovipositor width has hardly changed between the species, D. suzukii ovipositor length is almost double that of D. melanogaster. We show that this difference mostly arises in a 6-h time window during pupal development. We observe that the developing ovipositors of the two species comprise an almost identical number of cells, with a similar profile of cell shapes and orientations. After cell division stops, we find that the ovipositor area continues to grow in both species through the isotropic expansion of cell apical area and the anisotropic cellular reorganization of the tissue. Remarkably, we find that the lengthening of the D. suzukii ovipositor compared to that of D. melanogaster results from the combination of the accelerated expansion of apical cell size and the enhanced anisotropic rearrangement of cells in the tissue. Therefore, the quantitative fine-tuning of morphogenetic processes can drive evolutionary changes in organ size and shape.
Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) has been identified as a major physiological mechanism underlying the nutrient-dependent regulation of sexually selected weapon growth in animals. However, the molecular mechanisms that couple nutritional state with weapon growth remain largely unknown. Here, we show that one specific subtype of insulin-like peptide (ILP) responds to nutrient status and thereby regulates weapon size in the broad-horned flour beetle Gnatocerus cornutus. By using transcriptome information, we identified five G. cornutus ILP (GcorILP1–5) and two G. cornutus insulin-like receptor (GcorInR1, -2) genes in the G. cornutus genome. RNA interference (RNAi)-mediated gene silencing revealed that a certain subtype of ILP, GcorILP2, specifically regulated weapon size. Importantly, GcorILP2 was highly and specifically expressed in the fat body in a condition-dependent manner. We further found that GcorInR1 and GcorInR2 are functionally redundant but that the latter is partially specialized for regulating weapon growth. These results strongly suggest that GcorILP2 is an important component of the developmental mechanism that couples nutritional state to weapon growth in G. cornutus. We propose that the duplication and subsequent diversification of IIS genes played a pivotal role in the evolution of the complex growth regulation of secondary sexual traits.
Developmental, genetic and endocrine data from diverse taxa provide insight into the evolution of insect metamorphosis. We equate the larva–pupa–adult of the Holometabola to the pronymph–nymph–adult of hemimetabolous insects. The hemimetabolous pronymph is a cryptic embryonic stage with unique endocrinology and behavioural modifications that probably served as preadaptations for the larva. It develops in the absence of juvenile hormone (JH) as embryonic primordia undergo patterning and morphogenesis, the processes that were arrested for the evolution of the larva. Embryonic JH then drives tissue differentiation and nymph formation. Experimental treatment of pronymphs with JH terminates patterning and induces differentiation, mimicking the processes that occurred during the evolution of the larva. Unpatterned portions of primordia persist in the larva, becoming imaginal discs that form pupal and adult structures. Key transcription factors are associated with the holometabolous life stages: Krüppel-homolog 1 ( Kr-h1 ) in the larva, broad in the pupa and E93 in the adult. Kr-h1 mediates JH action and is found whenever JH acts, while the other two genes direct the formation of their corresponding stages. In hemimetabolous forms, the pronymph has low Broad expression, followed by Broad expression through the nymphal moults, then a switch to E93 to form the adult.
This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Developmental systems integrate inputs of variation from different origins into the observable variation of the resulting phenotype. Different components of phenotypic variation can be distinguished that correspond to those inputs, but the response of the system to each input factor can be modulated by other factors, so that there are interactions among the factors. This paper uses the concept of the target phenotype, introduced by Nijhout and Davidowitz to designate the expected phenotype for a given genotype and environment, to provide definitions and explanations of key concepts. This logic is put to use to explore the factors contributing to fluctuating asymmetry. To illustrate how genetic variation, phenotypic plasticity in response to temperature variation, and random developmental noise interact, this study uses computer simulations based on a simplified developmental model of a trait. The simulations show extensive interactions among the input factors, which can be explained by the non-linear nature of the developmental model. As a result, all the loci that control the developmental parameters end up affecting the resulting phenotypic trait, its reaction norm in response to temperature changes, and also its fluctuating asymmetry. Further, temperature (or possibly other environmental factors) can affect both trait values and the amount of fluctuating asymmetry without any involvement of stress. The model is broadly consistent with what is known from actual biological systems, and the results obtained from it have far-reaching implications for interpreting observations of the different types of phenotypic variation.
Insulin regulates blood glucose levels by binding its receptor and stimulating downstream proteins through the insulin receptor substrate (IRS). Impaired insulin signalling leads to metabolic syndrome, but the regulation of this process is not well understood. Here, we describe a novel insulin signalling regulatory pathway involving TAZ. TAZ upregulates IRS1 and stimulates Akt- and Glut4-mediated glucose uptake in muscle cells. Muscle-specific TAZ-knockout mice shows significantly decreased Irs1 expression and insulin sensitivity. Furthermore, TAZ is required for Wnt signalling-induced Irs1 expression, as observed by decreased Irs1 expression and insulin sensitivity in muscle-specific APC- and TAZ-double-knockout mice. TAZ physically interacts with c-Jun and Tead4 to induce Irs1 transcription. Finally, statin administration decreases TAZ, IRS1 level and insulin sensitivity. However, in myoblasts, the statin-mediated decrease in insulin sensitivity is counteracted by the expression of a constitutively active TAZ mutant. These results suggest that TAZ is a novel insulin signalling activator that increases insulin sensitivity and couples Hippo/Wnt signalling and insulin sensitivity. Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.
In most ectotherms, a reduction in developmental temperature leads to an increase in body size, a phenomenon known as the temperature size rule (TSR). In Drosophila melanogaster, temperature affects body size primarily by affecting critical size, the point in development when larvae initiate the hormonal cascade that stops growth and starts metamorphosis. However, while the thermal plasticity of critical size can explain the effect of temperature on overall body size, it cannot entirely account for the effect of temperature on the size of individual traits, which vary in their thermal sensitivity. Specifically, the legs and male genitalia show reduced thermal plasticity for size, while the wings show elevated thermal plasticity, relative to overall body size. Here, we show that these differences in thermal plasticity among traits reflect, in part, differences in the effect of temperature on the rates of cell proliferation during trait growth. Counterintuitively, the elevated thermal plasticity of the wings is due to canalization in the rate of cell proliferation across temperatures. The opposite is true for the legs. These data reveal that environmental canalization at one level of organization may explain plasticity at another, and vice versa.
Developmental transitions are often triggered by a neuroendocrine axis and can be contingent upon multiple organs achieving sufficient growth and maturation. How the neurodendocrine axis senses the size and maturity of peripheral organs is not known. In Drosophila larvae, metamorphosis is triggered by a sharp increase in the level of the steroid hormone ecdysone, secreted by the prothoracic gland (PG). Here, we show that the BMP2/4 ortholog Dpp can function as a systemic signal to regulate developmental timing. Dpp from peripheral tissues, mostly imaginal discs, can reach the PG and inhibit ecdysone biosynthesis. As the discs grow, reduced Dpp signaling in the PG is observed, consistent with the possibility that Dpp functions in a checkpoint mechanism that prevents metamorphosis when growth is insufficient. Indeed, upon starvation early in the third larval instar, reducing Dpp signaling in the PG abrogates the critical-weight checkpoint which normally prevents pupariation under these conditions. We suggest that increased local trapping of morphogen within tissues as they grow would reduce circulating levels and hence provide a systemic readout of their growth status.
Body size is a quantitative trait that is closely associated to fitness and under the control of both genetic and environmental factors. While developmental plasticity for this and other traits is heritable and under selection, little is known about the genetic basis for variation in plasticity that can provide the raw material for its evolution. We quantified genetic variation for body size plasticity in Drosophila melanogaster by measuring thorax and abdomen length of females reared at two temperatures from a panel representing naturally segregating alleles, the Drosophila Genetic Reference Panel (DGRP). We found variation between genotypes for the levels and direction of thermal plasticity in size of both body parts. We then used a Genome-Wide Association Study (GWAS) approach to unravel the genetic basis of inter-genotype variation in body size plasticity, and used different approaches to validate selected QTLs and to explore potential pleiotropic effects. We found mostly “private QTLs”, with little overlap between the candidate loci underlying variation in plasticity for thorax versus abdomen size, for different properties of the plastic response, and for size versus size plasticity. We also found that the putative functions of plasticity QTLs were diverse and that alleles for higher plasticity were found at lower frequencies in the target population. Importantly, a number of our plasticity QTLs have been targets of selection in other populations. Our data sheds light onto the genetic basis of inter-genotype variation in size plasticity that is necessary for its evolution.
Significance
Nutritional condition during childhood significantly impacts physical growth and height as an adult; hence, elucidating nutritional elements and their underlying mechanisms that influence growth in juveniles has drawn increasing attention. We show that a humoral protein that binds insulin-like growth factor plays a critical role in the nutritional control of juvenile body growth and insulin signaling in Drosophila . This protein is found be regulated by a steroid maturation hormone in adipose tissue, and this hormone is further shown to be regulated by the nutritional condition of animals. This study unveils an endocrine pathway for juvenile body growth, and it may also facilitate understanding of the insulin-resistance phenomena often occurring during puberty.
Animal cells are thought to sense mechanical forces via the transcriptional co-activators YAP/TAZ, whose soleDrosophilahomolog is named Yorkie (Yki). In mammalian cells in culture, artificial mechanical forces induce nuclear translocation of YAP/TAZ. Here we show that physiological mechanical strain can also drive nuclear localisation of Yki and activation of Yki target genes in theDrosophilafollicular epithelium. Mechanical strain activates Yki by stretching the apical domain, reducing the concentration of apical Crumbs, Expanded, Kibra and Merlin and reducing apical Hippo kinase dimerisation. Overexpressing Hippo kinase to induce ectopic activation in the cytoplasm is sufficient to prevent Yki nuclear localisation even in flattened follicle cells. Conversely, blocking Hippo signalling inwartsclones causes Yki nuclear localisation even in columnar follicle cells. We find no evidence for involvement of other pathways such as Src42A kinase in regulation of Yki. Finally, our results in follicle cells appear generally applicable to other tissues, as nuclear translocation of Yki is also readily detectable in other flattened epithelial cells such as the peripodial epithelium of the wing imaginal disc, where it promotes cell flattening.
Insulin is present all across the animal kingdom. Its proper release after feeding is of extraordinary importance for nutrient uptake, regulation of metabolism, and growth. We used Drosophila melanogaster to shed light on the processes linking dietary leucine intake to insulin secretion. The Drosophila genome encodes 8 insulin-like peptides ("Dilps"). Of these, Dilp2 is secreted after the ingestion of a leucine-containing diet. We previously demonstrated that Minidiscs, related to mammalian system-L transporters, acts as a leucine sensor within the Dilp2-secreting insulin-producing cells ("IPCs") of the brain. Here, we show that a second leucine transporter, JhI-21, of the same family is additionally necessary for proper leucine sensing in the IPCs. Using calcium imaging and ex-vivo cultured brains we show that knockdown of JhI-21 in IPCs causes malfunction of these cells: they are no longer able to sense dietary leucine or to release Dilp2 in a leucine dependent manner. JhI-21 knockdown in IPCs further causes systemic metabolic defects including defective sugar uptake and altered growth. Finally, we showed that JhI-21 and Minidiscs have no cumulative effect on Dilp2 release. Since system-L transporters are expressed by mammalian β-cells our results could help to better understand the role of these proteins in insulin signaling.
Significance
The mechanisms that regulate organismal growth and coordinate it with the availability of nutrients were unknown until a few decades ago. We now know that one pathway—the mechanistic target of rapamycin (mTOR) pathway—is the major nutrient-sensitive regulator of growth in animals and plays a central role in physiology, metabolism, the aging process, and common diseases. This work describes the development of the mTOR field, from its origins in studies into the mechanism of action of the drug rapamycin to our increasingly sophisticated understanding of how nutrients are sensed.
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.
Variation in the quality and quantity of nutrition is a major contributor to phenotypic variation in animal populations. Although we know much of how dietary restriction impacts phenotype, and of the molecular-genetic and physiological mechanisms that underlie this response, we know much less of the effects of dietary imbalance. Specifically, although dietary imbalance and restriction both reduce overall body size, it is unclear whether both have the same effect on the size of individual traits. Here, we use the fruit fly Drosophila melanogaster to explore the effect of dietary food versus protein-to-carbohydrate ratio on body proportion and trait size. Our results indicate that body proportion and trait size respond differently to changes in diet quantity (food concentration) versus diet quality (protein-to-carbohydrate ratio), and that these effects are sex specific. While these differences suggest that Drosophila use at least partially distinct developmental mechanisms to respond to diet quality versus quantity, further analysis indicates that the responses can be largely explained by the independent and contrasting effects of protein and carbohydrate concentration on trait size. Our data highlight the importance of considering macronutrient composition when elucidating the effect of nutrition on trait size, at the levels of both morphology and developmental physiology.
Biologists have been fascinated with the extreme products of sexual selection for decades. However, relatively few studies have characterized patterns of selection acting on ornaments and weapons in the wild. Here, we measure selection on a wild population of weapon-bearing beetles (frog legged leaf beetles: Sagra femorata) for two consecutive breeding seasons. We consider variation in both weapon size (hindleg length), and in relative weapon size (deviations from the population average scaling relationship between hindleg length and body size), and provide evidence for directional selection on weapon size per se and stabilizing selection on a particular scaling relationship in this population. We suggest that whenever growth in body size is sensitive to external circumstance such as nutrition, then considering deviations from population-level scaling relationships will better reflect patterns of selection relevant to evolution of the ornament or weapon than will variation in trait size per se. This is because trait-size versus body-size scaling relationships approximate underlying developmental reaction norms relating trait growth with body condition in these species. Heightened condition-sensitive expression is a hallmark of the exaggerated ornaments and weapons favored by sexual selection, yet this plasticity is rarely reflected in the way we think about – and measure – selection acting on these structures in the wild. This article is protected by copyright. All rights reserved
Wing polymorphism contributes significantly to the success of a wide variety of insects. However, its underlying molecular mechanism is less well understood. The migratory planthopper (BPH), Nilaparvata lugens , is one of the most extensively studied insects for wing polymorphism, due to its natural features of short- and long-winged morphs. Using the BPH as an example, we first surveyed the environmental cues that possibly influence wing developmental plasticity. Second, we explained the molecular basis by which two insulin receptors (InR1 and InR2) act as switches to determine alternative wing morphs in the BPH. This finding provides an additional layer of regulatory mechanism underlying wing polymorphism in insects in addition to juvenile hormones. Further, based on a discrete domain structure between InR1 and InR2 across insect species, we discussed the potential roles by which they might contribute to insect polymorphism. Last, we concluded with future directions of disentangling the insulin signalling pathway in the BPH, which serves as an ideal model for studying wing developmental plasticity in insects.
This article is part of the themed issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’.
Coordination of organ growth during development is required to generate fit individuals with fixed proportions. We recently identified Drosophila Dilp8 as a key hormone in coupling organ growth with animal maturation. In addition, dilp8 mutant flies exhibit elevated fluctuating asymmetry (FA) demonstrating a function for Dilp8 in ensuring developmental stability. The signals regulating Dilp8 activity during normal development are not yet known. Here, we show that the transcriptional co-activators of the Hippo (Hpo) pathway, Yorkie (Yki, YAP/TAZ) and its DNA-binding partner Scalloped (Sd), directly regulate dilp8 expression through a Hpo-responsive element (HRE) in the dilp8 promoter. We further demonstrate that mutation of the HRE by genome-editing results in animals with increased FA, thereby mimicking full dilp8 loss of function. Therefore, our results indicate that growth coordination of organs is connected to their growth status through a feedback loop involving Hpo and Dilp8 signalling pathways.
Damage to Drosophila melanogaster imaginal discs activates a regeneration checkpoint that (1) extends larval development and (2) coordinates the regeneration of the damaged disc with the growth of undamaged discs. These two systemic responses to damage are both mediated by Dilp8, a member of the insulin/insulin-like growth factor/relaxin family of peptide hormones, which is released by regenerating imaginal discs. Growth coordination between regenerating and undamaged imaginal discs is dependent on Dilp8 activation of nitric oxide synthase (NOS) in the prothoracic gland (PG), which slows the growth of undamaged discs by limiting ecdysone synthesis. Here we demonstrate that the Drosophila relaxin receptor homolog Lgr3, a leucine-rich repeat-containing G-protein-coupled receptor, is required for Dilp8-dependent growth coordination and developmental delay during the regeneration checkpoint. Lgr3 regulates these responses to damage via distinct mechanisms in different tissues. Using tissue-specific RNA-interference disruption of Lgr3 expression, we show that Lgr3 functions in the PG upstream of NOS, and is necessary for NOS activation and growth coordination during the regeneration checkpoint. When Lgr3 is depleted from neurons, imaginal disc damage no longer produces either developmental delay or growth inhibition. To reconcile these discrete tissue requirements for Lgr3 during regenerative growth coordination, we demonstrate that Lgr3 activity in both the CNS and PG is necessary for NOS activation in the PG following damage. Together, these results identify new roles for a relaxin receptor in mediating damage signaling to regulate growth and developmental timing.
Insulin/IGF signaling (IIS) in Drosophila melanogaster is propagated by eight Drosophila insulin-like peptides (dilps) and is regulated by nutrition. To understand how dietary protein and sugar affect dilp expression, we followed the analytical concepts of the Nutritional Geometric Framework, feeding Drosophila adults media comprised of seven protein-to-carbohydrate ratios at four caloric concentrations. Transcript levels of all dilps and three IIS-regulated genes were measured. Each dilp presented a unique pattern upon a bivariate plot of sugar and protein. Dilp2 expression was greatest upon diets with low protein-to-carbohydrate ratio regardless of total caloric value. Dilp5 expression was highly expressed at approximately a 1:2 protein-to-carbohydrate ratio and its level increased with diet caloric content. Regression analysis revealed that protein-to-carbohydrate ratio and the interaction between this ratio and caloric content significantly affects dilp expression. The IIS-regulated transcripts 4eBP and InR showed strikingly different responses to diet composition: 4eBP was minimally expressed except when elevated at low caloric diets. InR expression increased with protein level, independent of caloric content. Values of published life history traits measured on similar diets revealed correlations between egg production and the expression of dilp8 4eBP, while low protein-to-carbohydrate ratio diets associated with long lifespan correlated with elevated dilp2. Analyzing how nutient composition associates with dilp expression and IIS reveals that nutritional status is modulated by different combinations of insulin-like peptides, and these features variously correlate to IIS-regulated life history traits.
Measurement of the serum concentration of insulin-like growth factor-I (IGF-l) is generally used as a screening investigation for disorders of the growth hormone (GH)/IGF-I axis in children and adolescents with short stature. IGF-I concentration is sensitive to short-term and chronic alterations in the nutritional state, and the interpretation of IGF-I measurements requires knowledge of the child's nutritional status. In this review, we summarize the effects of nutrition on the GH/IGF-I axis, and review the clinical implications of these interactions throughout childhood, both in under-nutrition and over-nutrition.
Author
Genetic studies in Drosophila have elucidated conserved signaling pathways and environmental factors that together control organismal size. In humans, hundreds of genes are associated with height variation, but these associations have not been performed in a controlled environment. As a result we are still lacking an understanding of the mechanisms creating size variability within a species. Here, under carefully controlled environmental conditions, we identify naturally occurring genetic variants that are associated with size diversity in Drosophila. We identify a cluster of associations close to the kek1 locus, a well-characterized growth regulator, but otherwise find that most variants are located in or close to genes that do not belong to the conserved pathways but may interact with these in a biological network. We validate 33 novel growth regulatory genes that participate in diverse cellular processes, most notably cellular metabolism and cell polarity. This study is the first genome-wide association analysis of natural variants underlying size in Drosophila and our results complement the knowledge we have accumulated on this trait from mutational studies of single genes.
X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.
How different organs in the body sense growth perturbations in distant tissues to coordinate their size during development is poorly understood. Here we mutate an invertebrate orphan relaxin receptor gene, the Drosophila Leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), and find body asymmetries similar to those found in insulin-like peptide 8 (dilp8) mutants, which fail to coordinate growth with developmental timing. Indeed, mutation or RNA intereference (RNAi) against Lgr3 suppresses the delay in pupariation induced by imaginal disc growth perturbation or ectopic Dilp8 expression. By tagging endogenous Lgr3 and performing cell type-specific RNAi, we map this Lgr3 activity to a new subset of CNS neurons, four of which are a pair of bilateral pars intercerebralis Lgr3-positive (PIL) neurons that respond specifically to ectopic Dilp8 by increasing cAMP-dependent signalling. Our work sheds new light on the function and evolution of relaxin receptors and reveals a novel neuroendocrine circuit responsive to growth aberrations.
Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes-a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.
Animals have a determined species-specific body size that results from the combined action of hormones and signaling pathways regulating growth rate and duration. In Drosophila, the steroid hormone ecdysone controls developmental transitions, thereby regulating the duration of the growth period. Here we show that ecdysone promotes the growth of imaginal discs in mid-third instar larvae, since imaginal discs from larvae with reduced or no ecdysone synthesis are smaller than wild type due to smaller and fewer cells. We show that insulin-like peptides are produced and secreted normally in larvae with reduced ecdysone synthesis, and upstream components of insulin/insulin-like signaling are activated in their discs. Instead, ecdysone appears to regulate the growth of imaginal discs via Thor/4E-BP, a negative growth regulator downstream of the insulin/insulin-like growth factor/Tor pathways. Discs from larvae with reduced ecdysone synthesis have elevated levels of Thor, while mutations in Thor partially rescue their growth. The regulation of organ growth by ecdysone is evolutionarily conserved in hemimetabolous insects, as shown by our results obtained using Blattella germanica. In summary, our data provide new insights into the relationship between components of the insulin/insulin-like/Tor and ecdysone pathways in the control of organ growth.
Juvenile hormones (JHs) play a major role in controlling development and reproduction in insects and other arthropods. Synthetic JH-mimicking compounds such as methoprene are employed as potent insecticides against significant agricultural, household and disease vector pests. However, a receptor mediating effects of JH and its insecticidal mimics has long been the subject of controversy. The bHLH-PAS protein Methoprene-tolerant (Met), along with its Drosophila melanogaster paralog germ cell-expressed (Gce), has emerged as a prime JH receptor candidate, but critical evidence that this protein must bind JH to fulfill its role in normal insect development has been missing. Here, we show that Gce binds a native D. melanogaster JH, its precursor methyl farnesoate, and some synthetic JH mimics. Conditional on this ligand binding, Gce mediates JH-dependent gene expression and the hormone's vital role during development of the fly. Any one of three different single amino acid mutations in the ligand-binding pocket that prevent binding of JH to the protein block these functions. Only transgenic Gce capable of binding JH can restore sensitivity to JH mimics in D. melanogaster Met-null mutants and rescue viability in flies lacking both Gce and Met that would otherwise die at pupation. Similarly, the absence of Gce and Met can be compensated by expression of wild-type but not mutated transgenic D. melanogaster Met protein. This genetic evidence definitively establishes Gce/Met in a JH receptor role, thus resolving a long-standing question in arthropod biology.
The dynamics of growth and the timing of release of the brain's prothoracicotropic hormone (PTTH) in final instar larvae of Manduca sexta are consistent with the following hypothesis. When a 5th-stage larva reaches a critical weight of about 5 g an unidentified process is initiated which requires 24 h to be completed. At the completion of this process the brain is rendered competent to release PTTH. The actual release of PTTH is gated by the photoperiod and occurs when the gate opens during the very next photophase.
Evolution of relative organ size is the most prolific source of morphological diversity, yet the underlying molecular mechanisms that modify growth control are largely unknown. Models where organ proportions have undergone recent evolutionary changes hold the greatest promise for understanding this process. Uniquely among Drosophila species, D. prolongata displays a dramatic, male‐specific increase in the size of its forelegs relative to other legs. By comparing leg development between males and females of D. prolongata and its closest relative D. carrolli, we show that the exaggerated male forelegs are produced by a sex‐ and segment‐specific increase in mitosis during the final larval instar. Intersegmental compensatory control, where smaller leg primordia grow at a faster rate, is observed in both species and sexes. However, the equlibrium growth rates that determine the final relative proportion between the first and second legs have shifted in male D. prolongata compared both to conspecific females and to D. carrolli. We suggest that the observed developmental changes that produce new adult proportions reflect an interplay between conserved growth coordination mechanisms and evolving organ‐specific growth targets. This article is protected by copyright. All rights reserved
Bivariate morphological scaling relationships describe how the sizes of two traits co-vary among adults in a population. In as much as body shape is reflected by the relative size of various traits within the body, morphological scaling relationships capture how body shape varies with size, and therefore have been used widely as descriptors of morphological variation within and among species. Despite their extensive use, there is continuing discussion over which line-fitting method should be used to describe linear morphological scaling relationships. Here I argue that the 'best' line-fitting method is the one that most accurately captures the proximate developmental mechanisms that generate scaling relationships. Using mathematical modeling, I show that the 'best' line-fitting method depends on the pattern of variation among individuals in the developmental mechanisms that regulate trait size. For Drosophila traits, this pattern of variation indicates that major axis regression is the best line-fitting method. For morphological traits in other animals, however, other line-fitting methods may be more accurate. I provide a simple web-based application for researchers to explore how different line-fitting methods perform on their own morphological data.
The Hippo Pathway comprises a vast network of components that integrate diverse signals including mechanical cues and cell surface or cell-surface-associated molecules to define cellular outputs of growth, proliferation, cell fate, and cell survival on both the cellular and tissue level. Because of the importance of the regulators, core components, and targets of this pathway in human health and disease, individual components were often identified by efforts in mammalian models or for a role in a specific process such as stress response or cell death. However, multiple components were originally discovered in the Drosophila system, and the breakthrough of conceiving that these components worked together in a signaling pathway came from a series of Drosophila genetic screens and fundamental genetic and phenotypic characterization efforts. In this chapter, we will review the original discoveries leading to the conceptual framework of these components as a tumor suppressor network. We will review chronologically the early efforts that established our initial understanding of the core machinery that then launched the growing and vibrant field to be discussed throughout later chapters of this book.
Tissue growth needs to be properly controlled for organs to reach their correct size and shape, but the mechanisms that control growth during normal development are not fully understood. We report here that the activity of the Hippo signaling transcriptional activator Yorkie gradually decreases in the central region of the developing Drosophila wing disc. Spatial and temporal changes in Yorkie activity can be explained by changes in cytoskeletal tension and biomechanical regulators of Hippo signaling. These changes in cellular biomechanics correlate with changes in cell density, and experimental manipulations of cell density are sufficient to alter biomechanical Hippo signaling and Yorkie activity. We also relate the pattern of Yorkie activity in older discs to patterns of cell proliferation. Our results establish that spatial and temporal patterns of Hippo signaling occur during wing development, that these patterns depend upon cell-density modulated tissue mechanics, and that they contribute to the regulation of wing cell proliferation.
Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ∼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N ∼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P < 1 × 10-8), including 1185 height-associated SNPs and 751 BMI-associated SNPs located within loci not previously identified by these two GWAS. The near-independent genome-wide significant SNPs explain ∼24.6% of the variance of height and ∼6.0% of the variance of BMI in an independent sample from the Health and Retirement Study (HRS). Correlations between polygenic scores based upon these SNPs with actual height and BMI in HRS participants were ∼0.44 and ∼0.22, respectively. From analyses of integrating GWAS and expression quantitative trait loci (eQTL) data by summary-data-based Mendelian randomization, we identified an enrichment of eQTLs among lead height and BMI signals, prioritizing 610 and 138 genes, respectively. Our study demonstrates that, as previously predicted, increasing GWAS sample sizes continues to deliver, by the discovery of new loci, increasing prediction accuracy and providing additional data to achieve deeper insight into complex trait biology. All summary statistics are made available for follow-up studies.
Hippo signaling is regulated by biochemical and biomechanical cues that influence the cytoskeleton, but the mechanisms that mediate this have remained unclear. We show that all three mammalian Ajuba family proteins - AJUBA, LIMD1, and WTIP - exhibit tension-dependent localization to adherens junctions, and that both Lats family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization. This localization of Ajuba and Lats family proteins is also influenced by cell density, and by Rho activation. We establish that junctional localization of Lats kinases requires LIMD1, and that LIMD1 is also specifically required for the regulation of Lats kinases and YAP by Rho. Our results identify a biomechanical pathway that contributes to regulation of mammalian Hippo signaling, establish that this occurs through tension-dependent LIMD1-mediated recruitment and inhibition of Lats kinases in junctional complexes, and identify roles for this pathway in both Rho-mediated and density-dependent regulation of Hippo signaling.
The transcriptional co-activator YAP controls cell proliferation, survival, and tissue regeneration in response to changes in the mechanical environment. It is not known how mechanical stimuli such as tension are sensed and how the signal is transduced to control YAP activity. Here, we show that the LIM domain protein TRIP6 acts as part of a mechanotransduction pathway at adherens junctions to promote YAP activity by inhibiting the LATS1/2 kinases. Previous studies showed that vinculin at adherens junctions becomes activated by mechanical tension. We show that vinculin inhibits Hippo signaling by recruiting TRIP6 to adherens junctions and stimulating its binding to and inhibition of LATS1/2 in response to tension. TRIP6 competes with MOB1 for binding to LATS1/2 thereby blocking MOB1 from recruiting the LATS1/2 activating kinases MST1/2. Together, these findings reveal a novel pathway that responds to tension at adherens junctions to control Hippo pathway signaling.
Differential growth, the phenomenon where parts of the body grow at different rates, is necessary to generate the complex morphologies of most multicellular organisms. Despite this central importance, how differential growth is regulated remains largely unknown. Recent discoveries, particularly in insects, have started to uncover the molecular-genetic and physiological mechanisms that coordinate growth among different tissues throughout the body and regulate relative growth. These discoveries suggest that growth is coordinated by a network of signals that emanate from growing tissues and central endocrine organs. Here we review these findings and discuss their implications for understanding the regulation of relative growth and the evolution of morphology.
Coordination of growth between individual organs and the whole body is essential during development to produce adults with appropriate size and proportions [1, 2]. How local organ-intrinsic signals and nutrient-dependent systemic factors are integrated to generate correctly proportioned organisms under different environmental conditions is poorly understood. In Drosophila, Hippo/Warts signaling functions intrinsically to regulate tissue growth and organ size [3, 4], whereas systemic growth is controlled via antagonistic interactions of the steroid hormone ecdysone and nutrient-dependent insulin/insulin-like growth factor (IGF) (insulin) signaling [2, 5]. The interplay between insulin and ecdysone signaling regulates systemic growth and controls organismal size. Here, we show that Warts (Wts; LATS1/2) signaling regulates systemic growth in Drosophila by activating basal ecdysone production, which negatively regulates body growth. Further, we provide evidence that Wts mediates effects of insulin and the neuropeptide prothoracicotropic hormone (PTTH) on regulation of ecdysone production through Yorkie (Yki; YAP/TAZ) and the microRNA bantam (ban). Thus, Wts couples insulin signaling with ecdysone production to adjust systemic growth in response to nutritional conditions during development. Inhibition of Wts activity in the ecdysone-producing cells non-autonomously slows the growth of the developing imaginal-disc tissues while simultaneously leading to overgrowth of the animal. This indicates that ecdysone, while restricting overall body growth, is limiting for growth of certain organs. Our data show that, in addition to its well-known intrinsic role in restricting organ growth, Wts/Yki/ban signaling also controls growth systemically by regulating ecdysone production, a mechanism that we propose controls growth between tissues and organismal size in response to nutrient availability.
The Hippo pathway is emerging as a key evolutionarily conserved signaling mechanism that controls organ size. Three membrane-associated proteins, Kibra, Merlin, and Expanded, regulate pathway activity, but the precise molecular mechanism by which they function is still poorly understood. Here we provide evidence that Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain, the medial apical cortex. Merlin and Kibra together recruit the adapter protein Salvador, which in turn recruits the core kinase Hippo. In addition, we show that Crumbs has a dual effect on Hippo signaling. Crumbs promotes the ability of Expanded to activate the pathway but also sequesters Kibra to downregulate Hippo signaling. Together, our findings elucidate the mechanism of Hippo pathway activation by Merlin and Kibra, identify a subcellular domain for Hippo pathway regulation, and demonstrate differential activity of upstream regulators in different subcellular domains.
Regulation of final organ size is a complex developmental process that involves the integration of systemic and organ-specific processes. Previously, we have shown that in developing Drosophila, perturbing the growth of one imaginal disc – the parts of a holometabolous larva that become the external adult organs – retards growth of other discs and delays development, resulting in tight inter-organ growth coordination and the generation of a correctly proportioned adult. Whether different parts of the same imaginal disc similarly coordinate their growth to generate a functioning adult organ is, however, unclear. In this study, we use the wing imaginal disc in Drosophila to study and identify mechanisms of intra-organ growth coordination. We generate larvae in which the two compartments of the wing imaginal disc have ostensibly different growth rates (wild-type or growth-perturbed). We find that there is tightly coordinated growth between the wild-type and growth-perturbed compartments, where growth of the wild-type compartment is retarded to match that of the growth-perturbed compartment. Crucially, this coordination is disrupted by application of exogenous 20-hydroxyecdysone (20E), which accelerates growth of the wild-type compartment. We further elucidate the role of 20E signaling in growth coordination by showing that in wild-type discs, compartment-autonomous up-regulation of 20E signaling accelerates compartment growth and disrupts coordination. Interestingly, growth acceleration through exogenous application of 20E is inhibited with suppression of the Insulin/Insulin-like Growth Factor Signaling (IIS) pathway. This suggests that an active IIS pathway is necessary for ecdysone to accelerate compartment growth. Collectively, our data indicate that discs utilize systemic mechanisms, specifically ecdysone signaling, to coordinate intra-organ growth.
Juvenile hormone (JH) is a key insect growth regulator frequently involved in modulating phenotypically plastic traits such
as caste determination in eusocial species, wing polymorphisms in aphids, and mandible size in stag beetles. The jaw morphology
of stag beetles is sexually-dimorphic and condition-dependent; males have larger jaws than females and those developing under
optimum conditions are larger in overall body size and have disproportionately larger jaws than males raised under poor conditions.
We have previously shown that large males have higher JH titers than small males during development, and ectopic application
of fenoxycarb (JH analog) to small males can induce mandibular growth similar to that of larger males. What remains unknown
is whether JH regulates condition-dependent trait growth in other insects with extreme sexually selected structures. In this
study, we tested the hypothesis that JH mediates the condition-dependent expression of the elaborate horns of the Asian rhinoceros
beetle, Trypoxylus dichotomus. The sexually dimorphic head horn of this beetle is sensitive to nutritional state during larval development. Like stag beetles,
male rhinoceros beetles receiving copious food produce disproportionately large horns for their body size compared with males
under restricted diets. We show that JH titers are correlated with body size during the late feeding and early prepupal periods,
but this correlation disappears by the late prepupal period, the period of maximum horn growth. While ectopic application
of fenoxycarb during the third larval instar significantly delayed pupation, it had no effect on adult horn size relative
to body size. Fenoxycarb application to late prepupae also had at most a marginal effect on relative horn size. We discuss
our results in context of other endocrine signals of condition-dependent trait exaggeration and suggest that different beetle
lineages may have co-opted different physiological signaling mechanisms to achieve heightened nutrient-sensitive weapon growth.
In this review, the potential causes and consequences of adult height, a measure of cumulative net nutrition, in modern populations are summarized. The mechanisms linking adult height and health are examined, with a focus on the role of potential confounders. Evidence across studies indicates that short adult height (reflecting growth retardation) in low- and middle-income countries is driven by environmental conditions, especially net nutrition during early years. Some of the associations of height with health and social outcomes potentially reflect the association between these environmental factors and such outcomes. These conditions are manifested in the substantial differences in adult height that exist between and within countries and over time. This review suggests that adult height is a useful marker of variation in cumulative net nutrition, biological deprivation, and standard of living between and within populations and should be routinely measured. Linkages between adult height and health, within and across generations, suggest that adult height may be a potential tool for monitoring health conditions and that programs focused on offspring outcomes may consider maternal height as a potentially important influence.
The study of cranial variation has played an important role in primate systematics. Many different research strategies have been employed to investigate functional anatomy of the mammalian skull; but to fully understand the adaptive significance of cranial structure, it is necessary to consider cranial allometry, the relationship between the size and shape of the skull and body size. Over 20 years ago, le Gros Clark (1963, pp. 156–157) noted that
It is of the utmost importance to understand the implications of allometry in evolutionary development as well as in the growth of the individual.. As the result of allometric growth, the general shape and proportions of the skull (and also of other parts of the skeleton) may be very different in two quite closely related types. Such differences clearly have no great taxonomic value, since they may be related only to one major factor, i.e. body size.
The regulation of organ size is essential to human health, and has fascinated biologists for centuries. Key to the growth process is the ability of most organs to integrate organ-extrinsic cues (e.g. nutritional status, inflammatory processes) with organ-intrinsic information (e.g. genetic programs, local signals) into a growth response that adapts to changing environmental conditions and that ensures the size of an organ is coordinated with the rest of the body. Paired organs such as the vertebrate limbs and the long bones within them are excellent models for studying this type of regulation, as it is possible to manipulate one member of the pair and leave the other as an internal control. During development, growth plates at the end of each long bone produce a transient cartilage model that is progressively replaced by bone. Here, we review how proliferation and differentiation of cells within each growth plate is tightly controlled by mainly growth plate-intrinsic mechanisms that are additionally modulated by extrinsic signals. We also discuss the involvement of several signaling hubs in the integration and modulation of growth-related signals, and how they could confer remarkable plasticity to the growth plate. Indeed, long bones have a significant ability for "catch-up growth" to attain normal size after a transient growth delay. We propose that the characterization of catch-up growth, in light of recent advances in physiology and cell biology, will provide long sought clues into the molecular mechanisms that underlie organ growth regulation. Importantly, catch-up growth early in life is commonly associated with metabolic disorders in adulthood, and this association is not completely understood. Further elucidation of the molecules and cellular interactions that influence organ size coordination should allow development of novel therapies for human growth disorders that are non-invasive and have minimal side effects.
Early transplantation and grafting experiments suggest that body organs follow autonomous growth programs [1-3], therefore pointing to a need for coordination mechanisms to produce fit individuals with proper proportions. We recently identified Drosophila insulin-like peptide 8 (Dilp8) as a relaxin and insulin-like molecule secreted from growing tissues that plays a central role in coordinating growth between organs and coupling organ growth with animal maturation [4, 5]. Deciphering the function of Dilp8 in growth coordination relies on the identification of the receptor and tissues relaying Dilp8 signaling. We show here that the orphan receptor leucine-rich repeat-containing G protein-coupled receptor 3 (Lgr3), a member of the highly conserved family of relaxin family peptide receptors (RXFPs), mediates the checkpoint function of Dilp8 for entry into maturation. We functionally identify two Lgr3-positive neurons in each brain lobe that are required to induce a developmental delay upon overexpression of Dilp8. These neurons are located in the pars intercerebralis, an important neuroendocrine area in the brain, and make physical contacts with the PTTH neurons that ultimately control the production and release of the molting steroid ecdysone. Reducing Lgr3 levels in these neurons results in adult flies exhibiting increased fluctuating bilateral asymmetry, therefore recapitulating the phenotype of dilp8 mutants. Our work reveals a novel Dilp8/Lgr3 neuronal circuitry involved in a feedback mechanism that ensures coordination between organ growth and developmental transitions and prevents developmental variability.
Body-size constancy and symmetry are signs of developmental stability. Yet, it is unclear exactly how developing animals buffer
size variation. Drosophila insulin-like peptide Dilp8 is responsive to growth perturbations and controls homeostatic mechanisms that coordinately adjust
growth and maturation to maintain size within the normal range. Here we show that Lgr3 is a Dilp8 receptor. Through the use
of functional and adenosine 3′,5′-monophosphate assays, we defined a pair of Lgr3 neurons that mediate homeostatic regulation.
These neurons have extensive axonal arborizations, and genetic and green fluorescent protein reconstitution across synaptic
partners show that these neurons connect with the insulin-producing cells and prothoracicotropic hormone–producing neurons
to attenuate growth and maturation. This previously unrecognized circuit suggests how growth and maturation rate are matched
and co-regulated according to Dilp8 signals to stabilize organismal size.
Juvenile hormone (JH) is a central regulator of insect post-embryonic development and life history traits. The foundation of termites' sociality is their unravelled developmental plasticity. Through a unique diversity of moulting types, lower termites can remain immature workers by stationary and regressive development, become sterile soldiers, or neotenic replacement reproductives that inherit the natal breeding position. How can JH, the central morphogenic hormone, regulate this diversity besides the default progressive development into a winged sexual that is common to all insects? Here, I summarize our current understanding of the interactions between socio-environmental triggers, JH and linked gene pathways that underlie termite castes and division of labour. I end with a synthetic model that may serve as a guideline to future termite research.