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Mechano-Geometric Generative Rules of Morphogenesis
Abstract
The ideographical approach aimed at detecting specific causative relationships within the process of development prevails in modern embryology. The present work considers the possibilities of using the nomothetic approach aimed at putting forward nonspecific general laws based on the general scientific theory of self-organization and can be formulated in morphomechanical terms based on feedback links between passive and active mechanical stress. The perspectives of this approach and the involvement of genetic factors in the regulation of feedback links are discussed.
... Conjointly with a strong evidence in support of the capability of mechanical forces to change gene expression (e.g., Oses et al. 2023), a different view emerges in which mechanical forces can drive morphogenesis and molecular pre-patterns may be downstream rather than upstream them. Under this framework, pre-patterns would not provide instructions as commonly assumed, but would harness the self-shaping potential of living tissues (Beloussov and Grabovsky 2007;Doursat et al. 2012;Beloussov 2012a). It is important to stress that morphomechanics is focused on morphogenesis, and therefore, it is compatible with the idea that gene regulatory networks can drive other developmental processes. ...
... By harnessing self-organization using gene regulatory networks, cells could generate complex, functional forms in a reproducible way (Beloussov and Grabovsky 2007;Doursat et al. 2012;Beloussov 2012a). However, these developmental programs are not as usually conceived. ...
... Here it is important to stress that, according to Beloussov (2008;2012a), the hyper-restoration response is not specifically biological (i.e. arbitrary), but it can be understood as the extension of the Le Chatelier principle for active matter (i.e., at far from equilibrium conditions). ...
Morphomechanics is based on the idea that living matter can mechanically self-organize into forms without the need for a pre-pattern, as recently supported by the physics of active matter. Here an extended view is proposed that integrates bioelectricity and differentiation waves as the mechanisms by which cells measure mechanical stress and couple morphogenesis and cell differentiation, respectively. Morphomechanics is a largely unexplored approach, which however could deeply transform our way of seeing nature.
... Conjointly with a strong evidence in support of the capability of mechanical forces to change gene expression (e.g., Oses et al. 2023), a different view emerges in which mechanical forces can drive morphogenesis and molecular pre-patterns may be downstream rather than upstream them. Under this framework, pre-patterns would not provide instructions as commonly assumed, but would harness the self-shaping potential of living tissues (Beloussov and Grabovsky 2007;Doursat et al. 2012;Beloussov 2012a). It is important to stress that morphomechanics is focused on morphogenesis, and therefore, it is compatible with the idea that gene regulatory networks can drive other developmental processes. ...
... By harnessing self-organization using gene regulatory networks, cells could generate complex, functional forms in a reproducible way (Beloussov and Grabovsky 2007;Doursat et al. 2012;Beloussov 2012a). However, these developmental programs are not as usually conceived. ...
... Here it is important to stress that, according to Beloussov (2008;2012a), the hyper-restoration response is not specifically biological (i.e. arbitrary), but it can be understood as the extension of the Le Chatelier principle for active matter (i.e., at far from equilibrium conditions). ...
Morphomechanics is based on the idea that living matter can mechanically self-organize into forms without the need for a pre-pattern, as recently supported by the physics of active matter. Here an extended view is proposed that integrates bioelectricity and differentiation waves as the mechanisms by which cells measure mechanical stress and couple morphogenesis and cell differentiation, respectively. Morphomechanics is a largely unexplored approach, which however could deeply transform our way of seeing nature.
... When living matter is conceived as a mechanically active medium, common morphological motifs of embryos can arise by mechanical interactions only, i.e., pre-patterns are dispensable (Taber 2008;Beloussov 2012c;Hoffmann et al. 2022 may be downstream rather than upstream them. Under this framework, pre-patterns would not provide instructions as commonly assumed, but would harness the self-shaping potential of living tissues (Beloussov and Grabovsky 2007;Doursat et al. 2012;Beloussov 2012a). It is important to stress that morphomechanics is focused on morphogenesis, and therefore, it is compatible with the idea that gene regulatory networks can drive other developmental processes. ...
... By harnessing self-organization using gene regulatory networks, cells could generate complex, functional forms in a reproducible way (Beloussov and Grabovsky 2007;Doursat et al. 2012;Beloussov 2012a). However, these developmental programs are not as usually conceived. ...
... Here it is important to stress that, according to Beloussov (2008;2012a), the hyper-restoration response is not specifically biological (i.e. arbitrary), but it can be understood as the extension of the Le Chatelier principle for active matter (i.e., at far from equilibrium conditions). ...
Morphomechanics is based on the idea that living matter can mechanically self-organize into forms without the need for a pre-pattern, as recently supported by the physics of active matter. Here an extended view is proposed that integrates bioelectricity and differentiation waves as the mechanisms by which cells measure mechanical stress and couple morphogenesis and cell differentiation, respectively. Morphomechanics is a largely unexplored approach, which however could deeply transform our way of seeing nature.
... During development, organisms emerge as the result of a complex set of interactions among cells, with anatomical order and functionality being the result of cellular activities. While genomes specify the cellular hardware (proteins), it is the software (cellular activity) studied by developmental biologists that is ultimately responsible for the organism's overall structure and behavior [14][15][16][17][18]. ...
Biological genotypes do not code directly for phenotypes; developmental physiology is the control layer that separates genomes from capacities ascertained by selection. A key aspect is cellular competency, since cells are not passive materials but descendants of unicellular organisms with complex context-sensitive behavioral capabilities. To probe the effects of different degrees of cellular competency on evolutionary dynamics, we used an evolutionary simulation in the context of minimal artificial embryogeny. Virtual embryos consisted of a single axis of positional information values provided by cells’ ‘structural genes’, operated upon by an evolutionary cycle in which embryos’ fitness was proportional to monotonicity of the axial gradient. Evolutionary dynamics were evaluated in two modes: hardwired development (genotype directly encodes phenotype), and a more realistic mode in which cells interact prior to evaluation by the fitness function (“regulative” development). We find that even minimal ability of cells with to improve their position in the embryo results in better performance of the evolutionary search. Crucially, we observed that increasing the behavioral competency masks the raw fitness encoded by structural genes, with selection favoring improvements to its developmental problem-solving capacities over improvements to its structural genome. This suggests the existence of a powerful ratchet mechanism: evolution progressively becomes locked in to improvements in the intelligence of its agential substrate, with reduced pressure on the structural genome. This kind of feedback loop in which evolution increasingly puts more effort into the developmental software than perfecting the hardware explains the very puzzling divergence of genome from anatomy in species like planaria. In addition, it identifies a possible driver for scaling intelligence over evolutionary time, and suggests strategies for engineering novel systems in silico and in bioengineering.
... Whereas chemical selforganization leads to the spontaneous generation of chemical patternswhich can be subsequently translated into 3D forms -, mechanical self-organization leads to the spontaneous generation of 3D forms directly, without the need for a chemical pre-pattern. Adding an invariance to morphogenesis as those described in physics, the idea of mechanical self-organization challenges the view that all aspects of biological form are contingent (Beloussov 2012;Beloussov and Grabovsky 2007). Will be this farreaching, risky and largely unexplored idea be funded in the near future? ...
During embryogenesis, the spherical inner cell mass (ICM) proliferates in the confined environment of a blastocyst. Embryonic stem cells (ESCs) are derived from the ICM, and mimicking embryogenesis in vitro , mouse ESCs (mESCs) are often cultured in hanging droplets. This promotes the formation of a spheroid as the cells sediment and aggregate owing to increased physical confinement and cell–cell interactions. In contrast, mESCs form two-dimensional monolayers on flat substrates and it remains unclear if the difference in organization is owing to a lack of physical confinement or increased cell–substrate versus cell–cell interactions. Employing microfabricated substrates, we demonstrate that a single geometric degree of physical confinement on a surface can also initiate spherogenesis. Experiment and computation reveal that a balance between cell–cell and cell–substrate interactions finely controls the morphology and organization of mESC aggregates. Physical confinement is thus an important regulatory cue in the three-dimensional organization and morphogenesis of developing cells.
Embryonic development, which inspired the first theories of biological form, was eventually excluded from the conceptual framework of the Modern Synthesis as irrelevant. A major question during the last decades has centred on understanding whether new advances in developmental biology are compatible with the standard view or whether they compel a new theory. Here, I argue that the answer to this question depends on which concept of morphogenesis is held. Morphogenesis can be conceived as (1) a chemically driven or (2) a mechanically driven process. According to the first option, genetic regulatory networks drive morphogenesis. According to the second, morphogenesis results from an invariant tendency of embryonic tissues to restore changes in mechanical stress. While chemically driven morphogenesis allows an extension of the standard view, mechanically driven morphogenesis would deeply transform it. Which of these hypotheses has wider explanatory power is unknown. At present, the problem of biological form remains unsolved.
The article is an attempt of a theoretical analysis of the most important physiological laws of ontogeny and their applicability to the process of adaptation to physical exercise as a result of sports training. The hypothesis of this analysis is that the basic physiological principles (laws) of the organism development can be used in the construction of sports training. Indeed, for the long-term adaptation are important principles of heterochrony and of periodization, while other systemic patterns that are typical for ontogeny cannot be observed in the process of adaptation to exercise or have some specific features of manifestation.
Any theoretical construction in morphological modeling is useful only when it can be linked to the practice. Any formalism is not optimal for describing the processes of morphogenesis, if it is not comparable with the shape of tissue structures. Thus, it is necessary to find the best approximation for the correct comparison of the experimental and theoretical results. Proposed in this paper, the use of test functions for genetic algorithms, evolutionary programming, and swarm optimization for the approximation of the morphogenesis of cellular structures and their models is a mathematical step towards the implementation of the thesis of the analyzed article author (Gradov O.V., 2011), deduced not precise enough. There are other ways of analytical approximation for this case, but they have no fundamental differences in terms of their ease of use in mathematical biology. Achieved in this way comparability of morphometric and model histogenetic-morphogenetic data can be used in mathematical and morphological analysis and modeling in histology and embryology.
Morphogen patterns are viewed as being affected by epithelial sheet geometry in early development. As the total area of the (closed) sheet changes, the changing geometry acts back in turn to change the morphogen pattern. A number of constraints are given on the functional form of the Gauss and Mean curvatures, considered as functions of the morphogen concentrations and their derivatives. It is shown that the constraints are sufficient to motivate a convincing dependence of the two curvatures on the morphogen concentrations.
The question of how spatial structures and order are generated in the developing organism is one of the most challenging areas of biological research today. Much useful work has been done, principally by observing pattern regulation occurring after an experimental disturbance, but the underlying mechanisms — the multiplicity of molecular, cellular and tissue interactions taking place still remain obscure. This book shows which types of molecular interaction are able to account for well known and representative results documented in the literature. The mechanisms proposed are illustrated by precise, yet simply understood mathematical models, a means profitably applied for illuminating complex systems in many other disciplines.
The book begins by discussing mechanisms which have the ability to generate biological patterns, and goes on to consider how these mechanisms are used to generate positional information. A detailed comparison of the general theory with insect development is presented, and further chapters review the generation of subpatterns and how cells respond. Also considered are mechanisms for the activation of particular genes, which arc seen to be compatible with developmental alteration induced by a known class of mutants. The book concludes with a collection of FORTRAN computer programs which allow a simulation of the assumed interactions.
The precise mathematical treatment of biological dada presented here represents the first attempt to formulate a coherent theory of pattern formation during development. It will certainly stimulate further research, and will be read with interest by developmental biologists and those interested in mathematical modelling of complex systems.
We report on an experimental and theoretical study of phospholipid vesicles at small reduced volume. In this regime, vesicle shapes are non-axisymmetric and resemble starfish. To calculate these shapes, we minimize bending energy under constraints on area, volume and mean curvature on a triangulated surface. We find a multitude of locally stable starfish that have practically the same energy but look very different. Each starfish is build up from basically three different units: a core, several cylindrical arms and spherical caps at the end of these arms.
One of the elementary processes in morphogenesis is the formation of a spatial pattern of tissue structures, starting from almost homogeneous tissue. It will be shown that relatively simple molecular mechanisms based on auto- and cross catalysis can account for a primary pattern of morphogens to determine pattern formation of the tissue. The theory is based on short range activation, long range inhibition, and a distinction between activator and inhibitor concentrations on one hand, and the densities of their sources on the other. While source density is expected to change slowly, e.g. as an effect of cell differentiation, the concentration of activators and inhibitors can change rapidly to establish the primary pattern; this results from auto- and cross catalytic effects on the sources, spreading by diffusion or other mechanisms, and degradation.Employing an approximative equation, a criterium is derived for models, which lead to a striking pattern, starting from an even distribution of morphogens, and assuming a shallow source gradient. The polarity of the pattern depends on the direction of the source gradient, but can be rather independent of other features of source distribution. Models are proposed which explain size regulation (constant proportion of the parts of the pattern irrespective of total size). Depending on the choice of constants, aperiodic patterns, implying a one-to-one correlation between morphogen concentration and position in the tissue, or nearly periodic patterns can be obtained. The theory can be applied not only to multicellular tissues, but also to intracellular differentiation, e.g. of polar cells.The theory permits various molecular interpretations. One of the simplest models involves bimolecular activation and monomolecular inhibition. Source gradients may be substituted by, or added to, sink gradients, e.g. of degrading enzymes. Inhibitors can be substituted by substances required for, and depleted by activation.Sources may be either synthesizing systems or particulate structures releasing activators and inhibitors.Calculations by computer are presented to exemplify the main features of the theory proposed. The theory is applied to quantitative data on hydra — a suitable one-dimensional model for pattern formation — and is shown to account for activation and inhibition of secondary head formation.
The ecotoxicological properties of sediments from reservoir R-11 of the Techa River cascade are studied in comparison to the
Shershni reservoir. Radiochemical analysis of sediment and water samples from R-11 show that the radioactivity of the sediments
ranges from 240 to 360 kBq/dm3 dry weight for 90Sr and from 10 to 161 kBq/dm3 dry weight for 137Cs. The absorbed doses for Oligochaeta from R-11 are calculated on the basis of radiochemical data. The hydrobiological studies
include (1) study of the population density and diversity of Oligochaeta species in the reservoirs and (2) laboratory bioassay
of sediments with Tubifex tubifex as a biomonitor species. The results indicate that the Oligochaeta population density in R-11 is less than in the Shershni
reservoir. No significant effects of the absorbed dose rate on population density, survival rate, or fertility are found in
a laboratory Tubificidae bioassay of R-11 sediments. However, a decrease in fertility is noted in experiments at a higher
absorbed dose.
KeywordsOligochaeta–bottom sediments–bioindication–bioassay–absorbed dose–Techa reservoir cascade
A large repertoire of spatiotemporal activity patterns in the brain is the basis for adaptive behaviour. Understanding the mechanism by which the brain's hundred billion neurons and hundred trillion synapses manage to produce such a range of cortical configurations in a flexible manner remains a fundamental problem in neuroscience. One plausible solution is the involvement of universal mechanisms of emergent complex phenomena evident in dynamical systems poised near a critical point of a second-order phase transition. We review recent theoretical and empirical results supporting the notion that the brain is naturally poised near criticality, as well as its implications for better understanding of the brain.
Active particles contain internal degrees of freedom with the ability to take
in and dissipate energy and, in the process, execute systematic movement.
Examples include all living organisms and their motile constituents such as
molecular motors. This article reviews recent progress in applying the
principles of nonequilibrium statistical mechanics and hydrodynamics to form a
systematic theory of the behaviour of collections of active particles -- active
matter -- with only minimal regard to microscopic details. A unified view of
the many kinds of active matter is presented, encompassing not only living
systems but inanimate analogues. Theory and experiment are discussed side by
side.
Living cells sense the rigidity of their environment and adapt their activity to it. In particular, cells cultured on elastic substrates align their shape and their traction forces along the direction of highest stiffness and preferably migrate towards stiffer regions. Although numerous studies investigated the role of adhesion complexes in rigidity sensing, less is known about the specific contribution of acto-myosin based contractility. Here we used a custom-made single-cell technique to measure the traction force as well as the speed of shortening of isolated myoblasts deflecting microplates of variable stiffness. The rate of force generation increased with increasing stiffness and followed a Hill force-velocity relationship. Hence, cell response to stiffness was similar to muscle adaptation to load, reflecting the force-dependent kinetics of myosin binding to actin. These results reveal an unexpected mechanism of rigidity sensing, whereby the contractile acto-myosin units themselves can act as sensors. This mechanism may translate anisotropy in substrate rigidity into anisotropy in cytoskeletal tension, and could thus coordinate local activity of adhesion complexes and guide cell migration along rigidity gradients.
Many important morphogenetic processes that take place in the development of an animal start from the segregation of a homogeneous layer of cells into a different number of the domains of columnar and flattened cells. In many cases, waves of cell shape transformation travel throughout embryonic tissues. A biomechanical model is presented which embraces both kinds of event. The model is based on the idea of interplay between short- and long-range factors. While the former promote the spreading of a given cell state along a cell row in the recalculation direction, long-range factors are associated with self-generated tensions which, after exceeding a certain threshold, induce active cell extension and hence the rise of tangential pressure. Different kinds of biologically realistic stationary structures, as well as various kinds of the running waves, can be modelled under different parameter values. Moreover, the current model can be coupled with the previous one (Beloussov and Grabovsky, Comput. Methods Biomech. Biomed. Eng., 6: 53-63 (2003)) permitting a common causal chain to be created, moving from the state of an initial homogeneous cell layer towards the complicated shapes of embryonic rudiments.
To form adherens junctions (AJ), cells first establish contact by sending out lamellipodia onto neighboring cells. We investigated the role of contacting cells in AJ assembly by studying an asymmetric AJ motif: finger-like AJ extending across the cell-cell interface. Using a cytoskeleton replica and immunofluorescence, we observed that actin bundles embedded in the lamellipodia are co-localized with stress fibers in the neighboring cell at the AJ. This suggests that donor lamellipodia present actin fingers, which are stabilized by acceptor lamellae via acto-myosin contractility. Indeed, we show that changes in actin network geometry promoted by Rac overexpression lead to corresponding changes in AJ morphology. Moreover, contractility inhibition and enhancement (via drugs or local traction) lead respectively to the disappearance and further growth of AJ fingers. Thus, we propose that receiving lamellae exert a local pull on AJ, promoting further polymerization of the donor actin bundles. In spite of different compositions, AJ and focal contacts both act as cellular mechanosensors.
A deep (although at the first glance naïve) question which may be addressed to embryonic development is why during this process quite definite and accurately reproduced successions of precise and complicated shapes are taking place, or why, in several cases, the result of development is highly precise in spite of an extensive variability of intermediate stages. This problem can be attacked in two different ways. One of them, up to now just slightly employed, is to formulate robust macroscopic generative laws from which the observed successions of shapes could be derived. Another one, which dominates in modern embryology, regards the development as a succession of highly precise 'micropatterns', each of them arising due to the action of specific factors, having, as a rule, nothing in common with each other. We argue that the latter view contradicts a great bulk of firmly established data and gives no satisfactory answers to the main problems of development. Therefore we intend to follow the first way. By doing this, we regard developing embryos as self-organized systems transpierced by feedbacks among which we pay special attention to those linked with mechanical stresses (MS). We formulate a hypothesis of so-called MS hyper-restoration as a common basis for the developmentally important feedback loops. We present a number of examples confirming this hypothesis and use it for reconstructing prolonged chains of developmental events. Finally, we discuss the application of the same set of assumptions to the first steps of egg development and to the internal differentiation of embryonic cells.
Published posthumously in 1888, this treatise by the first Cavendish Professor of Physics at Cambridge explores and explains the fundamental principles and laws that are the basis of elementary physics. Maxwell was at the forefront of physics and mathematics during the nineteenth century and his pioneering work brought together existing ideas to give 'a dynamical theory of the electromagnetic field'. This work inspired not only the applications of electromagnetic waves like fibre optics but also Einstein's theory of relativity. The text explains many of Newton's laws and the unifying concepts that govern a body and its motion. The increment in the complexity of topics allows one to build a solid understanding of the accepted laws of mathematical physics that explain topics like force, work, energy and the centre mass point of a material system. This logical guide and instruction is as timeless as the laws of physics that it explains.
Development of characteristic tissue patterns requires that individual cells be switched locally between different phenotypes or “fates;” while one cell may proliferate, its neighbors may differentiate or die. Recent studies have revealed that local switching between these different gene programs is controlled through interplay between soluble growth factors, insoluble extracellular matrix molecules, and mechanical forces which produce cell shape distortion. Although the precise molecular basis remains unknown, shape-dependent control of cell growth and function appears to be mediated by tension-dependent changes in the actin cytoskeleton. However, the question remains: how can a generalized physical stimulus, such as cell distortion, activate the same set of genes and signaling proteins that are triggered by molecules which bind to specific cell surface receptors. In this article, we use computer simulations based on dynamic Boolean networks to show that the different cell fates that a particular cell can exhibit may represent a preprogrammed set of common end programs or “attractors” which self-organize within the cell's regulatory networks. In this type of dynamic network model of information processing, generalized stimuli (e.g., mechanical forces) and specific molecular cues elicit signals which follow different trajectories, but eventually converge onto one of a small set of common end programs (growth, quiescence, differentiation, apoptosis, etc.). In other words, if cells use this type of information processing system, then control of cell function would involve selection of preexisting (latent) behavioral modes of the cell, rather than instruction by specific binding molecules. Importantly, the results of the computer simulation closely mimic experimental data obtained with living endothelial cells. The major implication of this finding is that current methods used for analysis of cell function that rely on characterization of linear signaling pathways or clusters of genes with common activity profiles may overlook the most critical features of cellular information processing which normally determine how signal specificity is established and maintained in living cells.
A quantitative study of changes in the shape of cells of double explants of the tectum of gastrule blastocoele of the spur-toed frog within the first four hours after the artificial bending of explants has been performed. It was found that, on the concave (contracted) side of explants, epithelial cells stretch out, and the apical surface of many of these cells contracts, whereas on the convex (stretched) side they remain isodiometric. The maximal difference between the values of the apical index of epithelial cells located on the concave and convex sides was observed after 4 h of the cultivation of explants. It was shown that, by 2 h, the artificially produced curvature of the bent explant increases. The endocytosis on the concave side is more active than on the convex (stretched) side. The results of experiments with the use of inhibitors simulating the behavior of the actomyosin complex showed that the unimpeded functioning of myosin I is more important for the apical contraction and elongation of cells than the proper structural organization of the actin backbone.
The paper addresses the formation of striking patterns within originally near-homogenous tissue, the process prototypical for embryology, and represented in particularly puristic form by cut sections of hydra regenerating a complete animal with head and foot. Essential requirements are autocatalytic, self-enhancing activation, combined with inhibitory or depletion effects of wider range - “lateral inhibition”. Not only de-novo-pattern formation, but also well known, striking features of developmental regulation such as induction, inhibition, and proportion regulation can be explained on this basis. The theory provides a mathematical recipe for the construction of molecular models with criteria for the necessary non-linear interactions. It has since been widely applied to different developmental processes.
The mutual arrangement of neural and mesodermal rudiments in artificially bent double explants of Xenopus laevis suprablastoporal areas was compared with that of intact explants. While some of the bent explants straightened or became spherical, most retained and actively reinforced the imposed curvature, creating folds on their concave sides and expanding convex surfaces. In the intact explants, the arrangement of neural and mesodermal rudiments exhibited a distinct antero-posterior polarity, with some variability. In the bent explants, this polarity was lost: the neural rudiments were shifted towards concave while the mesodermal tissues moved towards the convex side, embracing the neural rudiments in a horseshoe-shaped manner. We associate these drastic changes in neuro-mesodermal patterning with the active extension and contraction of the convex and concave sides, respectively, triggered by the imposed deformations. We speculate that similar events are responsible for the establishment of neuro-mesodermal patterns during normal development.
The mechanical behaviour of a closed layered membrane enclosing a structureless interior is considered. The shape of such an object in flaccid conditions is determined theoretically by assuming that it corresponds to the minimum value of the membrane bending energy. The symmetry breaking properties of this system are revealed. It is suggested that a continuous transition from an axisymmetrical shape involving mirror symmetry with regard to the equatorial plane of the object to the shape with polar asymmetry could be the primary event in establishing cell polarity.
The problem of pattern is considered in terms of how genetic information can be translated in a reliable manner to give specific and different spatial patterns of cellular differentiation. Pattern formation thus differs from molecular differentiation which is mainly concerned with the control of synthesis of specific macromolecules within cells rather than the spatial arrangement of the cells. It is suggested that there may be a universal mechanism whereby the translation of genetic information into spatial patterns of differentiation is achieved. The basis of this is a mechanism whereby the cells in a developing system may have their position specified with respect to one or more points in the system. This specification of position is positional information. Cells which have their positional information specified with respect to the same set of points constitute a field. Positional information largely determines with respect to the cells' genome and developmental history the nature of its molecular differentiation. The specification of positional information in general precedes and is independent of molecular differentiation. The concept of positional information implies a co-ordinate system and polarity is defined as the direction in which positional information is specified or measured. Rules for the specification of positional information and polarity are discussed. Pattern regulation, which is the ability of the system to form the pattern even when parts are removed, or added, and to show size invariance as in the French Flag problem, is largely dependent on the ability of the cells to change their positional information and interpret this change. These concepts are applied in some detail to early sea urchin development, hydroid regeneration, pattern formation in the insect epidermis, and the development of the chick limb. It is concluded that these concepts provide a unifying framework within which a wide variety of patterns formed from fields may be discussed, and give new meaning to classical concepts such as induction, dominance and field. The concepts direct attention towards finding mechanisms whereby position and polarity are specified, and the nature of reference points and boundaries. More specifically, it is suggested that the mechanism is required to specify the position of about 50 cells in a line, relatively reliably, in about 10 hours. The size of embryonic fields is, surprisingly, usually less than 50 cells in any direction.
The problem considered in this paper is whether conventional chemical machines can be used in living organisms. I first point out that, due to their molecular nature, living systems pose unique thermodynamic problems, particularly in relation to Maxwell's demon. I then show that these problems may be solved by introducing time into the fundamental statement of the second law so that it becomes valid at the molecular level. This proposal, while clarifying certain logical anomalies in classical thermodynamics, makes no difference to that science in practice. However, I deduce from this statement that there are only two general ways of obtaining useful work from a chemical reaction: the first, a “constrained equilibrium” mechanism, is that employed by conventional chemical engines, but the second, a “molecular energy” mechanism, which depends upon the rapidity of resonant energy-transfer, may not have been suggested before. I then argue that because the former mechanism is essentially macroscopic in character it cannot, in fact, be used in those biological processes, like muscular contraction or active transport, in which useful molecular work is done and that only the latter may be so used. I also suggest reasons why this conclusion has been overlooked. Muscular contraction is used to illustrate these arguments and it is shown that all models of this process so far proposed fall into the first category. Although it is possible to eliminate such models a priori, several examples are finally criticized in detail to clarify the points raised. It is shown that in fact each of these models would have to be a Maxwell's demon machine.
One mechanism by which spatial patterns of cell differentiation could be specified during embryonic development and regeneration is based on positional information. Cells acquire a positional value with respect to boundaries and then interpret this in terms of a programme determined by their genetic constitution and developmental history. The signals and the molecular basis of such a system have both been rather well conserved. Recent work has shown that cells can respond to quite small differences in the concentrations of molecules whose concentration could provide positional information.
Morphogenetic movements are closely regulated by the expression of developmental genes. Here I examine whether developmental gene expression can in turn be mechanically regulated by morphogenetic movements. I have analyzed the effects of mechanical stress on the expression of Twist, which is normally expressed only in the most ventral cells of the cellular blastoderm embryo under the control of the Dorsal morphogen gradient. At embryogenesis gastrulation (stage 7), Twist is also expressed in the anterior foregut and stomodeal primordia.
Submitting the early Drosophila embryo to a transient 10% uniaxial lateral deformation induces the ectopic expression of Twist around the entire dorsal-ventral axis and results in the ventralization of the embryo. This induction is independent of the Dorsal gradient and is triggered by mechanically induced Armadillo nuclear translocation. I also show that Twist is not expressed in the anterior foregut and stomodeal primordia at stage 7 in mutants that block the morphogenetic movement of germ-band extension. Because I can rescue the mutants with gentle compression of these cells, my interpretation is that the stomodeal-cell compression normally caused by the germ-band extension induces the expression of Twist. Correspondingly, laser ablation of dorsal cells in wild-type embryos relaxes stomodeal cell compression and reduces Twist expression in the stomodeal primordium. I also demonstrate that the induction of Twist in these cells depends on the nuclear translocation of Armadillo.
I propose that anterior-gut formation is mechanically induced by the movement of germ-band extension through the induction of Twist expression in stomodeal cells.
Commitment of stem cells to different lineages is regulated by many cues in the local tissue microenvironment. Here we demonstrate that cell shape regulates commitment of human mesenchymal stem cells (hMSCs) to adipocyte or osteoblast fate. hMSCs allowed to adhere, flatten, and spread underwent osteogenesis, while unspread, round cells became adipocytes. Cell shape regulated the switch in lineage commitment by modulating endogenous RhoA activity. Expressing dominant-negative RhoA committed hMSCs to become adipocytes, while constitutively active RhoA caused osteogenesis. However, the RhoA-mediated adipogenesis or osteogenesis was conditional on a round or spread shape, respectively, while constitutive activation of the RhoA effector, ROCK, induced osteogenesis independent of cell shape. This RhoA-ROCK commitment signal required actin-myosin-generated tension. These studies demonstrate that mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.
Gastrulation in amphibian embryos is a composition of several differently located morphogenetic movements which are perfectly coordinated with each other both in space and time. We hypothesize that this coordination is mediated by biomechanical interactions between different parts of a gastrulating embryo based upon the tendency of each part to hyper-restore the value of its mechanical stress. The entire process of gastrulation in amphibian embryos is considered as a chain of these mutually coupled reactions, which are largely dependent upon the geometry of a given embryo part. We divide gastrulation into several partly overlapped steps, give a theoretical interpretation for each of them, formulate the experiments for testing our interpretation and describe the experimental results which confirm our point of view. Among the predicted experimental results are: inhibition of radial cell intercalation by relaxation of tensile stresses at the blastula stage; inversion of convergent intercalation movements by relaxation of circumferential stresses at the early gastrula stage; stress-promoted reorientation of axial rudiments, and others. We also show that gastrulation is going on under a more or less constant average value of tensile stresses which may play a role as rate-limiting factors. A macro-morphological biomechanical approach developed in this paper is regarded as complementary to exploring the molecular machinery of gastrulation.
Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.
Although all bilaterian animals have a related set of Hox genes, the genomic organization of this gene complement comes in different flavors. In some unrelated species, Hox genes are clustered; in others, they are not. This indicates that the bilaterian ancestor had a clustered Hox gene family and that, subsequently, this genomic organization was either maintained or lost. Remarkably, the tightest organization is found in vertebrates, raising the embarrassingly finalistic possibility that vertebrates have maintained best this ancestral configuration. Alternatively, could they have co-evolved with an increased `organization' of the Hox clusters, possibly linked to their genomic amplification, which would be at odds with our current perception of evolutionary mechanisms? When discussing the why's and how's of Hox gene clustering, we need to account for three points: the mechanisms of cluster evolution; the underlying biological constraints; and the developmental modes of the animals under consideration. By integrating these parameters, general conclusions emerge that can help solve the aforementioned dilemma.
“See my son, here time becomes space” Gurnemanz, in Parsifal (R. Wagner)
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