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Laterality defects in conjoined twins
... The second and most commonly accepted theory, known as the "fission theory," describes incomplete division of the monozygotic embryonic disc around the primitive streak stage of development (days 13-14 after fertilization) [4]. One of the arguments supporting this theory is the incidence of mirror imaging in up to almost half of the thoracopagus and parapagus dicephalus conjoined twins, most frequently occurring in the right-sided twin [16]. Levin et al. [16] studied the cascade of secreted signals during gastrulation regulating left-right asymmetry. ...
... One of the arguments supporting this theory is the incidence of mirror imaging in up to almost half of the thoracopagus and parapagus dicephalus conjoined twins, most frequently occurring in the right-sided twin [16]. Levin et al. [16] studied the cascade of secreted signals during gastrulation regulating left-right asymmetry. They found that when twin primitive streaks form at an angle rather than completely parallel, these signals can interfere between both twins, causing randomization of situs in one of the twins, sometimes resulting in mirror imaging [16]. ...
... Levin et al. [16] studied the cascade of secreted signals during gastrulation regulating left-right asymmetry. They found that when twin primitive streaks form at an angle rather than completely parallel, these signals can interfere between both twins, causing randomization of situs in one of the twins, sometimes resulting in mirror imaging [16]. ...
Background:
Conjoined twinning is a rare congenital malformation with an incidence of about 1.5 per 100,000 births. Because no consensus has been reached regarding the dysmorphology, thorough descriptions of conjoined twins as part of teratological collections can be useful to increase knowledge of this congenital malformation. In this case report, we describe a parapagus dicephalus twin from the collection of the Department of Anatomy of the University Medical Center Utrecht in the Netherlands. External anatomical characteristics were assessed through a detailed macroscopic examination and internal characteristics by means of whole-body computed tomography and magnetic resonance imaging (3 Tesla).
Case presentation:
Macroscopic examination showed a Caucasian male parapagus dicephalus tripus tribrachius conjoined twin a type of conjoined twinning in which there are two heads side by side, one rump, and three upper and three lower limbs. In addition, anencephaly was observed in the left twin. Radiological imaging showed a normal central nervous system in the right twin and absence of the calvaria, cerebrum, diencephalon, and mesencephalon in the left twin. There was clear duplication of the vertebral column, rib cage, respiratory system, and gastrointestinal system at least up to and including the first part of the duodenum. The heart consisted of a monoatrium with two separate ventricles. There was a fused liver with a single gallbladder, a single spleen, three kidneys, two bladders, and duplication of the penis. The third upper and lower extremities were articulating with a fused glenoid and acetabulum, respectively. The third foot showed both polydactyly and syndactyly of the toes.
Conclusion:
This case report describes a unique case of a male dicephalus parapagus tripus tribrachus conjoined twin discordant for anencephaly. Radiological imaging proved to be an adequate noninvasive method to provide insights into the internal (dys)morphology of this specific specimen, improving its scientific and educational value. This approach could be generally applied to other teratological specimens, thereby strengthening arguments regarding pathogenetic hypotheses, which may lead to new or improved insights into both normal and abnormal embryonic development.
... When approximation increases, interaction aplasia becomes more prominent (Fig. 5). Suppression of the structure and/or organ formation is assumed to result from aberrant concentrations of morphogens in and around the two longitudinal axes conflicting their concentration gradients and/or their (molecular) pathways (Levin et al., 1996). Primordia become obliterated by these overlapping gradients and subsequently fail to form a developmental field (Machin, 1993;Spencer, 2003). ...
... It can be assumed that duplicated primordia are localized in a certain (pre)destined pattern, both following their own fate while inducing their own signaling pathways (Tabata and Takei, 2004). Subsequently, these signaling pathways could potentially interfere with each other and create dysmorphological phenotypes (Levin et al., 1996;Gilbert-Barness et al., 2003). It is known that the loss of functional mutations of genes expressed by the AVE results in the formation of extra primitive streaks (Schoenwolf et al., 2009). ...
In this paper we provide a comprehensive overview of multiple facets in the puzzling genesis of symmetrical conjoined twins. The etiopathogenesis of conjoined twins remains matter for ongoing debate and is currently cited—in virtually every paper on conjoined twins—as partial fission or secondary fusion. Both theories could potentially be extrapolated from embryological adjustments exclusively seen in conjoined twins. Adoption of these, seemingly factual, theoretical proposals has (unconsciously) resulted in crystallized patterns of verbal and graphic representations concerning the enigmatic genesis of conjoined twins. Critical evaluating on their plausibility and solidity remains however largely absent. As it appears, both the fission and fusion theories cannot be applied to the full range of conjunction possibilities and thus remain matter for persistent inconclusiveness.
We propose that initial duplication of axially located morphogenetic potent primordia could be the initiating factor in the genesis of ventrally, laterally and caudally conjoined twins. The mutual position of two primordia results in neo‐axial orientation and/or interaction aplasia. Both these embryological adjustments result in conjunction patterns that may seemingly appear as being caused by fission or fusion. However, as we will substantiate, neither fission nor fusion are the cause of most conjoined twinning types; rather what is interpreted as fission or fusion is actually the result of the twinning process itself. Furthermore, we will discuss the currently held views on the origin of conjoined twins and its commonly assumed etiological correlation with monozygotic twinning. Finally, considerations are presented which indicate that the dorsal conjunction group is etiologically and pathogenetically different from other symmetric conjoined twins. This leads us to propose that dorsally united twins could actually be caused by secondary fusion of two initially separate monozygotic twins. An additional reason for the ongoing etiopathogenetic debate on the genesis of conjoined twins is because different types of conjoined twins are classically placed in one overarching receptacle—which has hindered the quest for answers.
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... Pitx2 is a bicoid-like homeodomain transcription factor, which seems to be active via its N-terminal part (isoform Pitx2c; Simard et al., 2009). The model based on ectopic diffusion of asymmetric gene products such as Sonic hedgehog onto the right side of one of the embryos from its neighbor matched human data (Levin et al., 1996) and was directly tested in chick twins, correctly predicting the ectopic induction of Nodal on the right side of the left twin (F). ...
... An understanding of the molecular determinants of L and R identity provided a ready explanation for what is happening when two embryonic fields are conjoined (Fig. 4): the left-specific secreted signaling molecules (such as Nodal) can leak over and affect the right side of the adjacent twin. The predictions of this model were validated against chick experiments using induced twins, and the geometric requirements for mutual arrangement of the primary axes (that could allow side-by-side leak-over of signals) provided an explanation for why certain classes of human twins exhibit laterality disturbances and others do not (Levin et al., 1996). ...
While the external vertebrate body plan appears bilaterally symmetrical with respect to anterior-posterior and dorsal-ventral axes, the internal organs are arranged with a striking and invariant left-right asymmetry. This laterality is important for normal body function, as alterations manifest as numerous human birth defect syndromes. The left-right axis is set up very early during embryogenesis by an initial and still poorly understood break in bilateral symmetry, followed by a cascade of molecular events that was discovered 20 years ago in the chick embryo model. This gene regulatory network leads to activation of the pitx2 gene on the left side of the embryo which ultimately establishes asymmetric organogenesis of the heart, gut, brain, and other organs. In this review, we highlight the crucial contributions of the avian model to the discovery of the differential transcriptional cascades operating on the Left and Right sides, as well as to the physiological events operating upstream of asymmetric gene expression. The chick was not only instrumental in the discovery of mechanisms behind left-right patterning, but stands poised to facilitate inroads into the most fundamental aspects that link asymmetry to the rest of evolutionary developmental biology.
... [2][3][4] Laterality defects in conjoined twins have been studied widely on animal models. Levin et al. in 1996 proposed various theories on laterality based on a study on 167 pairs of conjoined twins obtained from the literature. In cases (69) where the twins were joined obliquely at the chest and/or abdomen (thoracopagi) or laterally at the chest (dicephali), one of the twins in 33 pairs had reversal in heart situs; however none of the twins (of 98 remaining) joined only at the head (craniopagi) or pelvis (ischiopagi) exhibited laterally defects. ...
... This may explain the occurrence of situs inversus with dextrocardia in our case as well. [5] Epigastric heteropagus conjoined twins, is an extremely rare condition, and only 44 cases have been previously reported in the world literature. [3,4] There may be an associated heart disease in 28-30% cases. ...
... Both hearts are examined, but because the left twin is the induced one, only its situs (outlined in yellow) reveals the effects of a treatment on a late-induced organizer. The heart of the primary twin (outlined in blue) can be randomized due to leaky morphogens from the leftsided twin (Levin et al., 1996;Levin and Nascone, 1997;Nascone and Mercola, 1997). Wildtype heart situs is indicated by an orange arrowhead; inverted heart situs is indicated by a white arrowhead. ...
... Twins can be induced by injections of mRNAs encoding transcription factors such as XSiamois, which initiate secondary axes only after MBT (stage 8), when zygotic transcription begins. One of the first studies to examine Xenopus twins observed that induced twins have proper LR patterning when localized on the left side of the body (Nascone and Mercola, 1997); the twin on the right is randomized due to cross-over of secreted Shh, Nodal, and Activin signaling at very late stages (post neurulation) (Levin et al., 1996). Nascone and Mercola proposed that late organizers, induced when thousands of cells were present, al., 2012) were never seen in our experiments. ...
A number of processes operating during the first cell cleavages enable the left-right (LR) axis to be consistently oriented during Xenopus laevis development. Prior work showed that secondary organizers induced in frog embryos after cleavage stages (i.e. conjoined twins arising from ectopic induced primary axes) correctly pattern their own LR axis only when a primary (early) organizer is also present. This instructive effect confirms the unique LR patterning functions that occur during early embryogenesis, but leaves open the question: which mechanisms that operate during early stages are also involved in the orientation of later-induced organizers? We sought to distinguish the two phases of LR patterning in secondary organizers (LR patterning of the primary twin and the later transfer of this information to the secondary twin) by perturbing only the latter process. Here, we used reagents that do not affect primary LR patterning at the time secondary organizers form to inhibit each of 4 mechanisms in the induced twin. Using pharmacological, molecular-genetic, and photo-chemical tools, we show that serotonergic and gap-junctional signaling, but not proton or potassium flows, are required for the secondary organizer to appropriately pattern its LR axis in a multicellular context. We also show that consistently-asymmetric gene expression begins prior to ciliary flow. Together, our data highlight the importance of physiological signaling in the propagation of cleavage-derived LR orientation to multicellular cell fields.
... Grâce à ces expériences de la nature, certains auteurs ont mis en évidence que la latéralisation droite/gauche est mise en place dès les premières divisions cellulaires [16,17]. Au contraire, l'asymétrie de la plupart des organes internes ne serait pas encore spécifique, ou du moins assez plastique à ce stade, puisque le reste du développement est parfaitement normal pour les deux jumeaux [16,17]. ...
... Grâce à ces expériences de la nature, certains auteurs ont mis en évidence que la latéralisation droite/gauche est mise en place dès les premières divisions cellulaires [16,17]. Au contraire, l'asymétrie de la plupart des organes internes ne serait pas encore spécifique, ou du moins assez plastique à ce stade, puisque le reste du développement est parfaitement normal pour les deux jumeaux [16,17]. ...
Cet article reprend les données récentes sur la gémellité humaine et tente d'expliquer combien elle constitue un moyen précieux d'étude de la croissance cranio-faciale. Ces expériences naturelles de la croissance peuvent donner des indices sur l'interaction entre génétique et environnement au cours du développement. MOTS CLÉS – Jumeaux / Croissance ABSTRACT – This article presents recent data about human twinning and explains how twin studies can bring precious informations about craniofacial growth. These natural experiences of growth phenomenon can give clues about genetic/environment interactions during development.
... Moreover, it remains unknown how and if duplicated left and right organizers, with their cilia dynamics, are influenced. It becomes more and more clear that it is essential to realize that conjoined twinning should be interpreted as a congenital malformation in itself that is secondarily influenced by abnormally united organs and superimposed effects of anomalous hemodynamics and molecular aberrations due to embryological and/or mechanical adjustments after twin formation [79,152,153]. Nonetheless, significant gaps still exist in our understanding of the exact mechanisms that initiate twin formation with or without additional (discordant) anomalies (see graphical abstract). Future approaches should not only focus on morphological and embryological expertise but likely entail a mixture of (molecular) cell biology and genetics. ...
A multitude of additional anomalies can be observed in virtually all types of symmetrical conjoined twins. These concomitant defects can be divided into different dysmorphological patterns. Some of these patterns reveal their etiological origin through their topographical location. The so-called shared anomalies are traceable to embryological adjustments and directly linked to the conjoined-twinning mechanism itself, inherently located within the boundaries of the coalescence area. In contrast, discordant patterns are anomalies present in only one of the twin members, intrin-sically distant from the area of union. These dysmorphological entities are much more difficult to place in a developmental perspective, as it is presumed that conjoined twins share identical intra-uterine environments and intra-embryonic molecular and genetic footprints. However, their existence testifies that certain developmental fields and their respective developmental pathways take different routes in members of conjoined twins. This observation remains a poorly understood phenomenon. This article describes 69 cases of external discordant patterns within different types of otherwise symmetrical mono-umbilical conjoined twins and places them in a developmental perspective and a molecular framework. Gaining insights into the phenotypes and underlying (bio-chemical) mechanisms could potentially pave the way and generate novel etiological visions in the formation of conjoined twins itself.
... Consequently, these conjoined twins often exhibit LR defects. 17,18 This underscores that separation of left and right signals is fundamental in early development for . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily conserved program in which a straight gut tube elongates and forms into its first loops. However, the gut tube requires guidance to loop in a reproducible manner. The dorsal mesentery (DM) connects the gut tube to the body and directs the lengthening gut into stereotypical loops via left-right (LR) asymmetric cellular and extracellular behavior. The LR asymmetry of the DM also governs blood and lymphatic vessel formation for the digestive tract, which is essential for prenatal organ development and postnatal vital functions including nutrient absorption. Although the genetic LR asymmetry of the DM has been extensively studied, a divider between the left and right DM has yet to be identified. Setting up LR asymmetry for the entire body requires a Lefty1 + midline barrier to separate the two sides of the embryo—without it, embryos have lethal or congenital LR patterning defects. Individual organs including the brain, heart, and gut also have LR asymmetry, and while the consequences of left and right signals mixing are severe or even lethal, organ-specific mechanisms for separating these signals are not well understood. Here, we uncover a midline structure composed of a transient double basement membrane, which separates the left and right halves of the embryonic chick DM during the establishment of intestinal and vascular asymmetries. Unlike other basement membranes of the DM, the midline is resistant to disruption by intercalation of Netrin4 (Ntn4). We propose that this atypical midline forms the boundary between left and right sides and functions as a barrier necessary to establish and protect organ asymmetry.
... It is interesting that in conjoined twins who are joined at the thorax or abdomen, one of the twins will show situs inversus (Ibid). This probably results from cross-signalling between the two primitive streaks in the embryonic disc (Levin et al, 1996). However, if there is only a partial reversal of position, as for example when the heart is biased to the right (dextrocardia) and all the other organs are in their usual positions, then clinical problems can arise because of the changed inter-relationships within the body. ...
... 10 The discovery of these cascades has also shed light on the cause of situs defects in conjoined twins. 17 Genetic deletions of KIF3-A or KIF3-B, two microtubule-dependent kinesin motor proteins, resulted in a randomization of the situs of the viscera. In case of non-functional KIF3, the cell-adhesion factors N-cadherin and βcatenin are not transported to the cell surface. ...
Situs inversus totalis is a rare congenital abnormality characterized by a mirror-image transposition of both the abdominal and the thoracic organs. While this anomaly is known since the ancient times, practicing doctors do not have much experience with it. Laterality is established early in development, and any failure in that process might lead to a wide variety of disorders which may be partial or complete. Situs solitus describes the normal anatomy, situs inversus is the complete reversal, and situs ambiguous is used for any other abnormality of left-right development. Sidedness is regulated by genes: over 100 genes have been linked to laterality defects. Frequency of situs inversus is 1:10,000 and is more frequent in males: 1.5:1. Advanced imaging modalities can be used to assess fine anatomical details, which play a crucial role in these cases to plan radiologic or surgical interventions. Percutaneous biliary procedures, portal vein embolization are really challenging procedures in SIT patients due to the mirror effect. As most surgeons are right-handed, SIT operations can cause difficulties: handling the instruments with their left hand or the pedals with their left foot can be uncomfortable Organ, especially liver transplantation represents an extraordinary surgical challenge. Solutions to overcome the anatomic differences include the use of segment or reduced size graft with rotation, modified piggy-back technique, side to-side caval anastomosis, and vascular conduit. Because of its rarity and special nature, surgical patients with situs inversus may require more flexibility and creativity from the surgical team.
... The closer the approximation and the more acute the angle, the more prominent the interaction aplasia. Suppression of structure and/or organ formation is assumed to result from aberrant concentrations of morphogens in and around the two longitudinal axes and conflicting (molecular) pathways (Levin, Roberts, Holmes, & Tabin, 1996). Primordia become obliterated by these overlapping gradients and consequently fail to form (Machin, 1993). ...
Shared anomalies, always located close to the area of coalescence and observable in virtually every type of conjoined twinning, are currently seen as separate anomalies caused by mostly unknown and seemingly unrelated pathways rather than being connected to the twinning mechanism itself. Therefore, most (case) reports about conjoined twins are mere descriptions of (external) dysmorphologies lacking reflections on the possible origin of their concomitant anomalies. As we will demonstrate in this article, shared anomalies are influenced, and in some cases solely and sequentially explained, by interaction aplasia and neo-axial orientation; two embryological mechanisms to which each set of conjoined twins is subjected and are responsible for their ultimate phenotypical fate. In this review we consider how the ventral, lateral and caudal conjunction types and their intermediates determine the phenotypic presentation of the twins, including patterns of shared malformations and anomalies, which in themselves can be indistinguishable from those encountered in singleton cases. Hence, it can be hypothesized that certain anomalies in singletons originate in a fashion similar to that in conjoined twins.
... show that while signals from one side of the embryo cannot cross the midline and affect the other side, they can affect another neighbouring embryo (Levin et al., 1996;Nascone and Mercola, 1997). ...
Mutant alleles of sneezy were identified during the first Tubingen and Boston large-scale systematic screens for recessive-zygotic mutations affecting embryogenesis in zebrafish. It affects differentiation of the notochord, pigmentation, fin formation and leads to widespread degeneration of the embryo in the mid hatching period at about 60 hpf. Using a positional cloning approach, I have identified coatomer subunit α (copa) as the gene mutated in sneezy. The coatomer complex, together with the small GTPase ARF1, constitutes the protein coat of COPI vesicles, an essential component of the early secretory pathway. In zebrafish, copa is expressed maternally and during the first 24 hpf shows ubiquitous zygotic expression. This maternal wild-type component is responsible for absence of defects prior to ±24 hpf By tissue transplantation, I show that α-COP function is required within the shield derivatives for normal notochord differentiation. In addition, we find that α-COP activity is required within the neural tube for normal melanophore development. At 24 hpf sneezy mutant embryos display an abnormal maintenance of early chordamesoderm marker gene expression. This correlates with a failure of the chordamesoderm to differentiate into notochord. EM studies of notochord cells in sneezy mutants and wild-type siblings show that the early secretory pathway is blocked in sneezy. This results in disruption of formation or maintenance of the perinotochordal basal lamina. This general block in transport, which may affect the elaboration of integral membrane receptors, leads to a failure in notochord differentiation and subsequent apoptosis. In addition, abnormally high levels of apoptosis occur in the floorplate and posterior dorsal neural tube. Apoptosis in the posterior dorsal neural tube correlates with the lack of pigmentation, in the posterior trunk of mutant embryos. At more anterior levels, where melanophores may survive, the failure to become pigmented probably arises from a failure of the Golgi apparatus, which normally generates the melanosomes.
... Study of embryological development within chick embryos confirms that this dextral bending of the heart loop is the first gross anatomical feature to show asymmetry. This is closely followed by rotation of the It is an interesting observation that in human conjoined twins joined at the abdomen or chest one of the twins has an increased probability of complete situs inversus compared to those joined at the head or pelvis (Levin, Roberts et al. 1996). This observation has also been confirmed in chick embryos. ...
Primary ciliary dyskinesia (PCD) is the term used to encompass the diseases known as Kartagener syndrome (OMIM 244000) and immotile cilia syndrome (OMIM 242650/242680/242670). PCD is an autosomal recessive disease with an estimated prevalence of 1 in 20,000. The main clinical features of PCD are recurrent sinopulmonary infections as a direct consequence of a primary abnormality of cilia. Cilia are highly complex organelles and this has led to the hypothesis that mutations in a number of different genes may lead to the PCD phenotype. At the time that this research project was begun none of the disease genes causing PCD had been identified. The aim of this project was to map and clone the gene(s) for PCD using a positional cloning strategy. This thesis describes the results of two genome screens; the first genome screen used the technique of homozygosity mapping in a large consanguineous German family. This highlighted 3 areas of interest which were then further evaluated in families that shared an identical ultrastructural phenotype. The results did not achieve statistical significance but suggested potential loci for PCD on chromosome 17q and chromosome 11q. The second genome screen was performed in individuals from the isolated community of the Faroe Islands. This screen revealed an area of interest on chromosome 16p. This area continues to be evaluated. During the course of this thesis a mutation in a gene that codes for an intermediate dynein (IC78) (Pennarun, Escudier et al. 1999) was identified and significant evidence for linkage was also found on chromosome 19q. (Meeks, Walne et al. 2000). In summary PCD is a genetically heterogeneous disease. Two loci have been published (Pennarun, Escudier et al. 1999) (Meeks, Walne et al. 2000) and at least two further potential loci have been identified as part of this thesis.
... With regard to the abnormal aortic artery and bifid renal pelvises in the case described here, we did not find in the indexed online literature any similar human or canine cases. Nevertheless, the malformed aorta and hypoplastic kidneys in the right twin correspond to the claim that in many human conjoined twins, the abnormalities are more severe in the right twin, despite these cases being abnormalities of laterality ( Levin, Roberts, Holmes, & Tabin, 1996). The similarity between human and canine cephalothoracopagus is another indication of a common evolutionary origin, and how the morphogenetic mechanisms of vertebrates, and particularly mammals, are highly conserved. ...
A female pair of conjoined twins of the Lhasa Apso canine breed was subjected to tomographic and anatomical examinations. The twins had only one head and neck. The two ribcages were joined, extending to the umbilicus, with duplicated structures thereafter. They had three thoracic limbs and two pelvic girdles with four limbs, as well as a number of abnormalities in their internal organs. The data obtained were compared with the rare canine cases reported so far and with human cases.
... Proteins such as activin, nodal and Sonic hedgehog form a cascade of secreted signals regulating rightleft asymmetry. During embryonic development in conjoined twins, the signalling cascade of the right embryo can influence the cascade of the left embryo resulting in randomisation of its situs and the occurrence of laterality defects (Levin et al. 1996). On the other hand, maternal gene Vg1 (TGF-beta family) was implicated in dorso-anterior development and left-right axis formation. ...
In this report, we present a rare case of cephalothoracopagus (monocephalic dithoracic) conjoined twins with anencephaly in pig. Conjoined Polish large white piglets were born at term after an uncomplicated birth. The litter consisted of 11 piglets. The conjoined twins were born alive, but died shortly after birth and were subjected to further investigation. Blood vessels of the heart were filled with LBS 3060 latex, and then the twins were fixed in 10% non-buffered formalin. Necropsy revealed the external and internal anatomy of the affected twins. Examinations demonstrated abnormalities of skeletal, digestive, cardiovascular, respiratory and nervous systems. The twins had a single head, neck and chest and were separated from the umbilicus caudally. They had four forelimbs and four hindlimbs. Examination of the skeleton revealed two complete vertebral columns connected with one skull. Two tongues and a cleft palate were present in the oral cavity. The conjoined twins had a single pharynx, oesophagus, stomach, duodenum, part of jejunum, spleen, liver and pancreas. The remaining part of the digestive system was doubled. Each piglet had a separate urogenital apparatus. The examination revealed only one heart with structural abnormalities. Two larynxes and tracheas were identified. The right twin had the right lung while the left twin had the left lung. To the authors' knowledge, this is the first detailed report of this type of conjoined twins in the pig.
... This disease is transmitted usually but not invariably in an autosomal recessive manner. It is found in X-linked pattern of inheritence and in identical twins 7,8 . Abnormalities in Lefty gene, nodal gene, ZIC 3, ACVR2B and Pitxz gene is identified but not obvious culprit for this left-right asymmetry 9,10 . ...
p>Situs inversus totalis is the mirror-image of normal position of the thoracic and abdominal viscera. It may be detected incidentally when the patient seek medical attention for other medical illness. From medico-legal points of view, this rare disorder is important in many ways for a junior physician to prevent a big mishap, especially surgical. Here, we report a case, who was 55- year-old, seeking medical attention for infective exacerbation of chronic obstructive pulmonary disease incidentally diagnosed as a case of situs inversus totalis.
Bangladesh Heart Journal 2016; 31(2) : 100-103</p
... Only a certain type of human conjoined twins, which together account for some 70% of cases [1], displays situs randomization in the right twin, namely twins in which the thorax is fused (dicephalic, thoracopagus). Twins joined at the head or pelvis, however, develop situs solitus in both twins [1,14,32]. Our experimental manipulations in Xenopus only allow for the generation of thoracopagus twins, which-like in humansshow strict randomization of the right twin. ...
Conjoined twins fused at the thorax display an enigmatic left-right defect: although left twins are normal, laterality is disturbed in one-half of right twins [1-3]. Molecularly, this randomization corresponds to a lack of asymmetric Nodal cascade induction in right twins [4]. We studied leftward flow [5, 6] at the left-right organizer (LRO) [7, 8] in thoracopagus twins in Xenopus, which displayed a duplicated, fused, and ciliated LRO. Cilia were motile and produced a leftward flow from the right LRO margin of the right to the left margin of the left twin. Motility was required for correct laterality in left twins, as knockdown of dynein motor dnah9 prevented Nodal cascade induction. Nodal was rescued by parallel knockdown of the inhibitor dand5 [9, 10] on the left side of the left twin. Lack of Nodal induction in the right twin, despite the presence of flow, was due to insufficient suppression of dand5. Knockdown of dand5 at the center of the fused LRO resulted in asymmetric Nodal cascade induction in the right twin as well. Manipulation of leftward flow and dand5 in a targeted and sided manner induced the Nodal cascade in a predictable manner, in the left twin, the right one, both, or neither. Laterality in conjoined twins thus was determined by cilia-driven leftward fluid flow like in single embryos, which solves a century-old riddle, as the phenomenon was already studied by some of the founders of experimental embryology, including Dareste [11], Fol and Warynsky [12], and Spemann and Falkenberg [13] (reviewed in [14]).
... The first molecular explanations for the asymmetry of body organs came from studies in the chick [23], with the identification of asymmetrically expressed genes, such as the left-sided Sonic hedgehog (Shh) and Nodal, the inductive and repressive relationships among these genes, and functional studies showing that aberrant expression of any of these was sufficient to randomize the situs of the heart, gut and other viscera [24,25]. These data not only helped explain organ laterality in normal development but also provided a mechanistic explanation for laterality disturbances long known to occur in conjoined twins [26]. The central component of the LR pathway was the left-sided cassette formed by Shh inducing expression of Nodal, which regulates Lefty, which subsequently induces Pitx2 [27][28][29]. ...
Consistent left–right (LR) asymmetry is a fundamental aspect of the bodyplan across phyla, and errors of laterality form an important class of human birth defects. Its molecular underpinning was first discovered as a sequential pathway of left- and right-sided gene expression that controlled positioning of the heart and visceral organs. Recent data have revised this picture in two important ways. First, the physical origin of chirality has been identified; cytoskeletal dynamics underlie the asymmetry of single-cell behaviour and patterning of the LR axis. Second, the pathway is not linear: early disruptions that alter the normal sidedness of upstream asymmetric genes do not necessarily induce defects in the laterality of the downstream genes or in organ situs . Thus, the LR pathway is a unique example of two fascinating aspects of biology: the interplay of physics and genetics in establishing large-scale anatomy, and regulative (shape-homeostatic) pathways that correct molecular and anatomical errors over time. Here, we review aspects of asymmetry from its intracellular, cytoplasmic origins to the recently uncovered ability of the LR control circuitry to achieve correct gene expression and morphology despite reversals of key ‘determinant’ genes. We provide novel functional data, in Xenopus laevis , on conserved elements of the cytoskeleton that drive asymmetry, and comparatively analyse it together with previously published results in the field. Our new observations and meta-analysis demonstrate that despite aberrant expression of upstream regulatory genes, embryos can progressively normalize transcriptional cascades and anatomical outcomes. LR patterning can thus serve as a paradigm of how subcellular physics and gene expression cooperate to achieve developmental robustness of a body axis.
This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.
... The first molecular explanations for the asymmetry of body organs came from studies in the chick [49], with the identification of asymmetricallyexpressed genes, such as the left-sided Sonic hedgehog (Shh) and Nodal, the inductive and repressive relationships among these genes, and functional studies showing that aberrant expression of any of these was sufficient to randomize the situs of the heart, gut, and other viscera [50,51]. These data not only helped explain organ laterality in normal development but also provided a mechanistic explanation for laterality disturbances long known to occur in conjoined twins [52]. The central component of the LR pathway was the left-sided cassette formed by Shh inducing expression of Nodal inducing expression of Lefty inducing expression of Pitx2 [53, 54, 55]. ...
Consistent left-right asymmetry is a fundamental aspect of the bodyplan across phyla, and errors of laterality form an important class of human birth defects. Its molecular underpinning was first discovered as a sequential pathway of left- and right-sided gene expression that controlled positioning of the heart and visceral organs. Recent data have revised this picture in two important ways. First, the physical origin of chirality has been identified; cytoskeletal dynamics underlie the asymmetry of single cell behavior and of patterning of the left-right axis. Second, the pathway is not linear: early disruptions that alter the normal sidedness of upstream asymmetric genes do not necessarily induce defects in the laterality of the downstream genes or in organ situs. Thus, the LR pathway is a unique example of two fascinating aspects of biology: the interplay of physics and genetics in establishing large-scale anatomy, and regulative (shape-homeostatic) pathways that correct errors of patterning over time. Here, we review aspects of asymmetry from its intracellular, cytoplasmic origins to the recently-uncovered ability of the LR control circuitry to achieve correct gene expression and morphology despite reversals of key ″determinant″ genes. We provide novel functional data, in Xenopus laevis, on conserved elements of the cytoskeleton that drive asymmetry, and repair of downstream gene expression anomalies over developmental time. LR patterning can thus serve as a paradigm of how subcellular physics and gene expression cooperate to achieve developmental robustness of a body axis.
... This type of union typically includes a shared heart as well (Kaufman, 2004). In cases where the hearts are not fused, one of the twins usually has reversal of heart sinus (Levin et al., 1996). However, we are unable confirm either in this case, as we did not perform any destructive investigation. ...
There are numerous records of conjoined twinning in humans and domesticated animals, but many fewer for wild animals because of the early death of conjoined twins. We here describe the incidental discovery and skeletal anatomy of a wild-caught bat fetus with two heads. To our knowledge, this is only the second conjoined bat fetus described, and the first conjoined Artibeus phaeotis. We also revisit the anatomy of the first conjoined bat that was described, a stillborn Eptesicus fuscus.
... The anomalies occur very early in the development of the embryo when zygote division rather than feto-fetal transfusion provides the pathogenic mechanism (Burn and Corney, 1984;Burn, 1991). Relevant to the role of MZ twinning in the pathogenesis of CA is that the heterotaxias and other cardiac anomalies are frequently found in conjoined twins and are influenced by the site of union of the twins (Cunniff et al., 1988;Gerlis et al., 1993;Levin et al., 1996). Also attributable to the division of the zygote, but of lesser clinical importance, is the mirror imaging phenomenon of hair whorls, birth marks and tooth eruption patterns that are frequently observed in MZ twins. ...
... The anomalies occur very early in the development of the embryo when zygote division rather than feto-fetal transfusion provides the pathogenic mechanism (Burn and Corney, 1984;Burn, 1991). Relevant to the role of MZ twinning in the pathogenesis of CA is that the heterotaxias and other cardiac anomalies are frequently found in conjoined twins and are influenced by the site of union of the twins (Cunniff et al., 1988;Gerlis et al., 1993;Levin et al., 1996). Also attributable to the division of the zygote, but of lesser clinical importance, is the mirror imaging phenomenon of hair whorls, birth marks and tooth eruption patterns that are frequently observed in MZ twins. ...
... Obliquely conjoined twins provide support for this hypothesis. In conjoined twins, the twin on the right frequently exhibits laterality deficits (Levin et al., 1996). Levin suggests the parallel orientation of the two primitive streaks allows activin on the right side of the left embryo to inhibit Shh on the left side of the right embryo. ...
Variation in hemispheric asymmetry of the planum temporale (PT) has been related to verbal ability. The degree to which genetic and environmental factors mediate PT asymmetry is not known. This study examined the heritability for planar asymmetry in 12 dizygotic (DZ) and 27 monozygotic (MZ) male twin pairs who were between 6 and 16 years of age. There was weak but positive evidence for heritability of planar asymmetry. Co-twin similarity for planar asymmetry and Sylvian fissure morphology increased when excluding twins discordant for writing hand and when excluding twins exhibiting birth weight differences >20% from the analyses. Birth weight differences were also related to twin differences in total cerebral volume, but not central sulcus asymmetry. These results suggest that exogenous perinatal factors affect the epigenesis of planar asymmetry development.
... The most extreme case of late monozygotic twinning results in incomplete separation of the twins. When conjoined human twins have distinct hearts, the right-sided twin commonly has dextrocardia (Levin et al., 1996). In nonconjoined monozygotic twins, situs inversus is rare but is probably more frequent than in singletons (Torgersen, 1950). ...
An unexpectedly high percentage of monozygotic twin pairs is discordant for handedness. Some of these twins show mirror-imaging of several ectodermally derived features. Both features of discordant left±right asymmetry may be caused by relatively late monozygotic twinning , when the original embryo has already lost its bilateral symmetry. Language lateralization is related to handedness and may therefore also be altered during the development of embryological asymmetry in some monozygotic twins. Language lateralization was measured with functional MRI in 12 monozygotic twin pairs who were concordant for handedness and in 13 monozygotic twin pairs discordant for handedness. Lateralization indices were calculated from individual language activation patterns. Correlations were calculated to test intra-pair resemblance for language lateralization. The intra-pair correlation for language lateralization was signi®cant in the handedness-concor-dant group, but not in the handedness-discordant group. In the handedness-discordant group, ®ve twin pairs were also discordant for cerebral dominance; the other twin pairs of discordant handedness exhibited remarkable similarity in language lateralization. The high intra-pair correlation for language lateralization in the handedness-concordant twins suggests a genetic basis for language lateralization. However, in monozy-gotic twin pairs of discordant handedness, discordance for language dominance occurs in a signi®cant number of twins. Discordant language dominance may be caused by a relatively late time of splitting of the original embryo, which disrupts the normal development of left± right asymmetry.
... It has always been a puzzle that the right twin of a laterally conjoined pair seems much more likely to have laterality defects. Levin et al. [3] suggest that there is 'cross-talk' between the signals of adjacent embryos. If primitive streaks are close together during early gastrulation, activin on the right of the left twin may not only down-regulate Shh in its own right node, but also cross to the left side of the right twin, resulting in Shh (and consequently nodal) being absent from the right twin. ...
Vertebrates have consistent differences between their left and right sides. In all species, nodal, a transforming growth factor β superfamily signalling protein, is involved in a late step in the pathways that specify such asymmetry in the embryo. Earlier components seem not so well conserved.
... It has been proposed that an explanation for the laterality defects might be found in consideration of interactions between signaling molecules in two adjacent primitive streaks. Analysis of spontaneous twins of chick embryos (Levin et al. 1996) by in situ hybridization with probes to asymmetric signaling factors such as Shh and Nodal have given rise to two models that are predictive with respect to which classes of conjoined twins should exhibit laterality defects, and which twin should be affected. For example, parallel streaks during early gastrulation could result in the right-sided Activin of the left embryo inhibiting the expression of Shh in the left side of the right embryo. ...
... cases of side-by-side twins (as in parapagus twins) the asymmetrically-expressed genes on one side of one twin might affect the development of the opposite side of the adjacent twin. Indeed, it was found that unlike the other types of twins, human twins connected side by side have significantly much higher incidences of laterality disturbances 28 . Levin et al. (1996) 28 examined spontaneous conjoined chicken twins of the parapagus type. One such example is shown inFigure 7B; note that the left twin has bilateral expression of the gene Nodal, which should normally only be expressed on the left side (as it is, in the right twin). These findings have suggested the following model which explains lateral ...
... Cardiac anomalies are to be expected in any type of conjoined twinning where the heart is topographically related to the plane of conjunction [Benirschke et al., 1978]. Indeed, Levin et al. [1996] pointed out that cardiac laterality defects occur in about half of the cases of thoracopagus and dicephalus but not in ischiopagus and craniopagus. The authors explain their observations in chick embryos by demonstrating that in CTs with parallel or near-parallel primitive streaks the cascade of secreted signals that induces normal left-right asymmetry in one twin, upsets the regulation in the other twin. ...
The Museum Vrolik collection of the Department of Anatomy and Embryology of the Academic Medical Center, University of Amsterdam, founded by Gerardus Vrolik (1775–1859) and his son Willem Vrolik (1801–1863), consists of more than 5,000 specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, the collection of congenital anomalies, comprising 360 specimens, was recatalogued and redescribed according to contemporary perspectives. The original descriptions, as far as preserved, were compared with the clinical, radiographic, and magnetic resonance imaging findings. We diagnosed 30 symmetrical conjoined twins (CTs), 11 parasitic CTs, and 16 acardiac twins. Within the group of symmetrical CTs, the following concomitant external anomalies were found in 15 specimens: neural tube defects, holoprosencephaly, cleft lip/ palate, umbilical hernia, omphalocele, cloacal exstrophy, peromelia, polydactyly, and facial abnormalities suggestive of a chromosomal abnormality. We discuss the results in the light of historical and contemporary explanations regarding conjoined twinning, including the opinions of Gerardus and Willem Vrolik and of Louis Bolk, one of their successors. Am. J. Med. Genet. 80:74–89, 1998. © 1998 Wiley-Liss, Inc.
There is an increasing demand for high-standard fetal and infant neuropathology examinations. Novel imaging techniques, development of new diagnostic methods and advances in genetics have stimulated the interest in gaining additional knowledge on developmental, perinatal and neonatal neuropathology. Approaching the subject from a practical standpoint, diagnostic templates for reports are provided in this essential guide to aid clinicians with different areas of expertise. Each chapter will includes numerous high-quality images, accompanied by explanatory legends from the authors' own experiences. Covering autopsy and tissue processing techniques, the authors discuss a range of disorders such as neural tube defects, brain tumours, storage disorders and many others. This book provides access to an online version on Cambridge Core, which can be accessed via the code printed on the inside of the cover. Compiling the latest advances in fetal and infant diagnostics and care, this book is a highly valuable educational resource.
Bislang haben wir uns vorwiegend auf die Flügel unseres Drachens (damit er fliegen kann), seine typische Physiologie (damit er Feuer speien kann) und sein Gehirn (das das ganze System steuern soll) konzentriert. Aber ein Drache braucht weit mehr als das. Vom Kopf bis zur Schanzspitze unseres Drachens gibt s viele weitere Merkmale, die ernsthafte Überlegungen verdienen.
Cambridge Core - Cardiovascular Medicine - Pathology of Heart Disease in the Fetus, Infant and Child - by Michael T. Ashworth
Cleft lip and palate is the most common craniofacial birth defect, and its etiology has been the focus of many reports in the literature. It is well accepted that both genetics and environment play a role in the condition; however, the authors still have not been able to translate what have been learned into clinical applications. This paper provides an interpretation of 2 possible mechanisms leading to cleft lip and palate in humans. First, the authors reflect on the known association between maternal cigarette smoking and risk for cleft lip and palate and the proposed hypoxic mechanism put forward to explain this association. Second, the authors reflect on the difference in frequency between left and right cleft lip and propose that without more extensive clinical definitions, it will be difficult to definitely unveil genetic targets that can be used for counseling.
Conjoined twins occur at low frequency in all vertebrates including humans. Many twins fused at the chest or abdomen display a very peculiar laterality defect: while the left twin is normal with respect to asymmetric organ morphogenesis and placement (situs solitus), the organ situs is randomized in right twins. Although this phenomenon has fascinated already some of the founders of experimental embryology in the 19th and early 20th century, such as Dareste, Fol, Warynsky and Spemann, its embryological basis has remained enigmatic. Here we summarize historical experiments and interpretations as well as current models, argue that the frog Xenopus is the only vertebrate model organism to tackle the issue, and outline suitable experiments to address the question of twin laterality in the context of cilia-based symmetry breakage.
Left–right asymmetries are highly prevalent throughout metazoan phyla, with bilaterally symmetrical organisms exhibiting well-conserved, consistently sided positioning and anatomy of visceral organs and central nervous system structures. Deviations from normal laterality constitute an important class of birth defects and much study has been devoted to the early mechanisms orienting the left–right axis during embryogenesis as well as lateralization of the brain. Far less understood are the potential links between laterality of the body and cognition, though recent work has begun to uncover a range of behaviors which are modified in organisms with altered left–right asymmetry. Here, we review regulatory events critical for the establishment of asymmetry and subsequent left–right patterning, using data from Xenopus, zebrafish, chick, Arabidopsis, and single cells, and discuss molecular and pharmacological reagents that disrupt these processes. We especially focus on behavioral assays which are sensitive to body laterality, presenting existing data for several model systems. Beyond classical conditioning and behavior screens, new automated machine vision platforms are powerful emerging tools to quantitatively examine the relationship between body asymmetry and lateralized and nonlateralized behaviors. This chapter serves as a primer for methods that allow the examination of cognitive and behavioral endpoints subsequent to molecular interventions in embryonic left–right asymmetry.
Bicephalia is one of the scarcest malformations reported in birds and needs to be fully investigated in chick embryos. Among 1500 fertilised eggs used to examine the primordial germ cells in 2-day and 5.5-day chick embryos Gallus gallus domesticus, bicephalia was found and the condition of the heads, the heart and other parts of the body was fully described. Each twin had its own head; hearts were not completely separated from each other and the rest of the bodies were externally unique. This investigation urges others including poultry farms to share their data on a bigger scale. It may also encourage the monitoring of abnormalities randomly seen during early chick embryogenesis and consideration of environmental factors when poultry farms are faced with high percentages of unsuccessful hatching. The report can shed some light on developmental processes and may also help to clarify why bicephalia is not more common.
One of the most significant recent findings in cardiac L-R development is that the earliest molecular events that determine cardiac orientation occur by cell-cell signaling pathways that do not involve the cardiac primordia. Genes that are not expressed within perspective heart cells have a profound effect on the formation of the heart. By RNA in situ hybridization analysis, at least six RNAs have been shown to be asymmetrically distributed along the L-R axis in chick embryos during gastrulation and neurula stages, predominantly either in or near Hensens's node (HN). Cell signaling genes activin βB, Sonic hedgehog, and a Nodal-related genes are asymmetrically expressed, as are a transmembrane receptor for activin and transcription factors HFNβ and Snrl1. Other genes, including the cell signaling gene cWnt-8c and the receptor patched have asymmetric expression patterns in HN. It is found that mutually exclusive asymmetric expressions of cNR1 and cSnrl then signal the heart and visceral primordia to provide orientation during subsequent asymmetric organogenesis. It is not known whether the pathway elucidated in chick embryos is conserved in other vertebrates. Some of the genes shown to have asymmetric expression patterns in chick embryos have been shown to have symmetric expression patterns in other embryos.
In 1861 Paul Broca discovered that, in most individuals, the left hemisphere of the brain is dominant for language. Taking language as an example, the first part of this book explains the normal development of bodily asymmetry and lateralization, its association with hand preference, genetic aspects, geographical differences and the influence of gender. The coverage then moves on to review the association between language lateralization and psychosis, describing findings in patients with schizophrenia to suggest the dominant hemisphere may fail to completely inhibit the language areas in the non-dominant half. The language allowed to 'release' from the right hemisphere can lead to psychotic symptoms including auditory verbal hallucinations and formal thought disorder. This book should be read by psychiatrists, neurologists and neuroscientists working in the field of psychosis and other brain scientists interested in laterality.
Coelomic cavities of vertebrates are lined by a mesothelium which develops from the lateral plate mesoderm. During development, the coelomic epithelium is a highly active cell layer, which locally is able to supply mesenchymal cells that contribute to the mesodermal elements of many organs and provide signals which are necessary for their development. The relevance of this process of mesenchymal cell supply to the developing organs is becoming clearer since genetic lineage tracing techniques have been developed in recent years. Body wall, heart, liver, lungs, gonads and gastrointestinal tract are populated by cells derived from the coelomic epithelium which contribute to their connective and vascular tissues, and sometimes to specialized cell types such as the stellate cells of the liver, the Cajal interstitial cells of the gut or the Sertoli cells of the testicle. In this review we collect information about the contribution of coelomic epithelium derived cells to visceral development, their developmental fates and signaling functions. The common features displayed by all these processes suggest that the epithelial-mesenchymal transition of the embryonic coelomic epithelium is an underestimated but key event of vertebrate development, and probably it is shared by all the coelomate metazoans. This article is protected by copyright. All rights reserved.
This chapter focuses on the progress that has been made in the past in the identification of genes that may play roles in the specification of left-right (L-R) asymmetry and cardiac looping in early vertebrate embryos. The morphological changes are summarized that occur during early heart development, genes that have been identified to be asymmetrically expressed before and during heart looping, embryonic manipulations that can affect looping, and mutations that randomize or reverse the direction of looping. It is found that Looping of the heart is the first morpological indication of L-R asymmetry in vertebrates. Several proteins, including TGF-β-related signaling molecules, bHLH transcription factors, zinc finger transcription factors, and ECM components are asymmetrically expressed both prior to and during the looping of the heart. The chapter also proposes a novel molecular model for the initial determination of the L-R asymmetry. Since heart looping represents the first morphological manifestation of L-R asymmetry in vertebrates, an intriguing goal for research on cardiac embryogenesis is to elucidate the specific signals that are used to translate molecular L-R asymmetry into architectural L-R asymmetry.
Conjoined twins are a very rare complication of monozygotic pregnancies, with thoraco-omphalopagus twins being the most common presentation. Prenatal diagnosis of this anomaly can be achieved in the early first trimester. The areas of union between the embryos and the presence of associated malformations should be carefully evaluated for parent counseling. We report a case of omphalopagus conjoined twins with shared megacystis and discuss the ultrasound findings and management of these cases. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound, 2013
Left–right (LR) patterning of the vertebrate embryo regulates heart, gut, and brain development. Three transient signaling centers in the embryo contribute to LR patterning: ciliated cells in the node/organizer/shield, the floorplate and notochord in the embryonic midline, and the lateral plate mesoderm. A cassette of asymmetrically expressed genes in the left lateral plate mesoderm is evolutionarily conserved and upstream of organ asymmetry. This cassette includes members of the TGF‐β signaling pathway family (Nodal and Lefty) and the transcription factor Pitx2. Here, we review two other signaling pathways hedgehog and fibroblast growth factor, which have been implicated in LR patterning but appear to have divergent roles in distinct classes of vertebrates.
Congenital malformations are the second childhood mortality cause in in Chile. The purpose of this study is to illustrate the use of advanced imaging techniques for diagnostic of congenital cardiac malformations on conjoined twins. Fetus malformated were preserved in a 10% formaldeide solution in Teratology Unit of Anatomy Department, Faculty of Medicine at University of Chile. This study begins with conventional techniques, such as X-rays and ultrasound of the thoraco- omphalopagus conjoined twins. The images obtained by CT and MR imaging were archived and worked by a computing program (Somavision) that allows an image to be selectively examined and dissected as well as the complete anatomically reconstruction in situ of systems and organs. The MR imaging was performed at Clinical Hospital JJ Aguirre of University of Chile, and the CT was done at Instituto Nacional del Cáncer, Santiago, Chile whom provided digitalized equip-ment and software for tridimentional cardiac reconstruction
Vertebrate development gives rise to systematic, normally reliably coordinated left-right asymmetries of body structure. This “handed asymmetry” of anatomy must take its ultimate origin from some chiral molecular assembly (one exhibiting no planes of symmetry and thus, having an intrinsic “handedness”) within the early embryo's cells. But which molecules are involved, how is their chiral property coordinately aligned among many cells, and how does it “seed” the differential cascades of gene expression that characterise right and left halves of the embryo? Recent molecular characterisations of mouse mutations that randomise or reverse body asymmetries have offered tantalising clues to the chiral initiator molecules, but the findings in a subsequent Cell paper (Nonaka S, Yosuke T, Okada Y, Takeda S, Harada K, Kanai Y, Kido M, Hirokawa N. Randomisation of left-right asymmetry due to loss of nodal cilia generating a leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998;95:829–837. [Reference 1]) may help us understand how the first gene expression asymmetries occur. BioEssays 21:537–541, 1999. © 1999 John Wiley & Sons, Inc.
Cephalothoracopagus embryos are conjoined twins, who share parts of their heads, necks and bodies. Our study aims at presenting a detailed morphological analysis of a cephalothoracopagus chick embryo of developmental stage 31. Because none of the existing theories can explain the genesis of the phenotype of this embryo, we also suggest a hypothesis, which explains it. Beside the cephalothoracopagus embryo, we investigated five control embryos. With the aid of the high-resolution episcopic microscopy (HREM) technique, we created digital volume data and three-dimensional (3D) computer models of the organs and arteries of the embryos. We used the 3D models for topological analysis and for measuring the diameters of the great intrathoracic arteries. The malformed embryo showed two body backs, each containing a notochord, spinal cord and dorsal aorta. The body backs continued into separated lower bodies. The embryo had a single, four-chambered heart, single respiratory tract and single upper alimentary tract. The topology of the pharyngeal arch arteries was normal, and the diameters of these arteries were similar to that of the control embryos. We classified the embryo we investigated as a yet unknown malformation and suggest a hypothesis explaining its genesis.
An individual's behavior is generated and modulated by the structure and function of the brain and body. Thus, an understanding of the embryonic processes which pattern the human organism is crucial to a complete understanding of cognition and behavior. The general plan of the human body and nervous system is bilaterally symmetric, but contains important and consistent asymmetries of the brain as well as of visceral organs such as the heart. Studies of human twins, together with animal models of twinning, have enabled an understanding, at the molecular genetic level, of key processes involved in the generation of the primary embryonic axis, and in the reliable establishment of embryonic left–right asymmetry. Several genes expressed in the early embryo in regions such as the nascent nervous system are asymmetrically expressed. The protein products of these genes function to specify the laterality of the brain, heart, stomach, gall bladder, etc. In conjoined twins, laterality disturbances arise because of interfering cross-talk of genetic signaling cascades between the twins. Nonconjoined twins likewise show interesting symmetry properties which shed light on mechanisms underlying asymmetric development. These molecular mechanisms have profound influence on the physical and cognitive development of the organism.
All vertebrates have normally consistent left–right asymmetries of structure, and abnormalities of this asymmetry in humans are clinically important.
Keywords:
handedness;
gene expression;
laterality;
heart looping;
gastrulation
The left-right body axis is defined relative to the dorsal-ventral and anterior-posterior body axes. Since left-right asymmetries are not randomly oriented with respect to dorsal-ventral and anterior-posterior spatial patterns, it is possible that a common mechanism determines all three axes in a coordinate manner. Two approaches were undertaken to determine whether alteration in dorsal-anterior development perturbs the left-right orientation of heart looping. Treatments known to decrease dorsal-anterior development in Xenopus laevis, UV irradiation during the first cell cycle or Xwnt-8 DNA injections into dorsal blastomeres, caused an increase in cardiac left-right reversals. The frequency of left-right reversal was correlated with the severity of dorsal-anterior perturbation and with the extent of anterior notochord regression. Injection of Xwnt-8 DNA into dorsal midline cells resulted in decreased dorsal-anterior development and a correlated increase in cardiac left-right reversals. In contrast, injection of Xwnt-8 DNA into cardiac progenitor blastomeres did not result in left-right reversals, and dorsal-anterior development and notochord formation were normal. Disrupting development of dorsal-anterior cells, including cells that give rise to the Organizer region and the notochord, results in the randomization of cardiac left-right asymmetry. These results suggest dorsal-anterior development and the regulation of left-right orientation are linked.
Vertebrates have characteristic and conserved left-right (L-R) visceral asymmetries, for example the left-sided heart. In humans, alterations of L-R development can have serious clinical implications, including cardiac defects. Although little is known about how the embryonic L-R axis is established, a recent study in the chick embryo revealed L-R asymmetric expression of several previously cloned genes, including Cnr-1 (for chicken nodal-related-1), and indicated how this L-R molecular asymmetry might be important for subsequent visceral morphogenesis. Here we show that nodal is asymmetrically expressed in mice at similar stages, as is Xnr-1 (for Xenopus nodal related-1) in frogs. We also examine nodal expression in two mouse mutations that perturb L-R development, namely situs inversus viscerum (iv), in which assignment of L-R asymmetry is apparently random and individuals develop either normally or are mirror-image-reversed (situs inversus), and inversion of embryonic turning (inv), in which all individuals develop with situs inversus. In both, nodal expression is strikingly affected, being reversed or converted to symmetry. These results further support a key role for nodal and nodal-related genes in interpreting and relaying L-R patterning information in vertebrates. To our knowledge, our results provide the first direct evidence that iv and inv normally function well before the appearance of morphological L-R asymmetry.
We have studied omphalopagus conjoined twins with a diamniotic monochorionic placenta. Although conjoined twins usually present in a single amniotic sac, one other example of diamniotic placenta has been reported in omphalopagus twins [Weston et al., 1990: Am J Med Genet 37:558–561]. Most theories concerning the pathogenesis of conjoined twinning exclude the possibility of diamniotic placentation. However, Spencer [1992: Teratology 45:591–602] recently elaborated a model for conjoined twinning based on duplication of organizing centers (primitive streaks) during gastrulation. We have considered the fate of embryonic membranes according to this model of omphalopagus twinning and show that diamniotic placentation is a predictable outcome. © 1994 Wiley-Liss, Inc.
A theoretical basis for the embyology of conjoined twins was formulated from clinical experience with ten cases and extensive review of pertinent embryologic and clinical literature, including over 500 cases. Regarding the age old question of fusion or fission , it is concluded that there is no known embryologic process by which conjoined twins can be formed by fission but firm evidence to support fusion in all cases. Whether the fusion occurs between embryos on one embryonic disc or on two is of no consequence since they are all monovular. Intact ectoderm will not fuse to intact ectoderm, and all seven types of conjoined twins are explained by seven possible sites of union in the early embryo. One new term is proposed: parapagus , from the Greek para , meaning “side,” combined with pagus , meaning “fixed”; this is the group formerly called dicephalus or diprosopos. These anterolaterally united parapagus twins must result from two nearly parallel notochords in close proximity; craniopagi and pygopagi from fusion at the cranial and caudal neuropores, respectively; cephalopagi and ischiopagi from union at the pharyngeal and cloacal membranes, respectively; thoracopagi from merging of the cardiac anlage; and omphalopagi from fusion of the umbilicus or of the edges of two embryonic discs in any area not including the above sites. Parasitic twins result from embryonic death of one twin, leaving various portions of the body vascularized by the surviving autosite.
The rarity of cases (2) not easily explained by the above theories, and the nearly 6% of twins with two umbilical cords arising from the placenta would seem to support these conclusions.
Should one wish to learn the methods of a conjurer, he might vainly watch the latter's customary repertoire, and, so long as everything went smoothly, might never obtain a clue to the mysterious performance, baffled by the precision of the manipulations and the complexity of the apparatus; if, however, a single error were made in any part or if a single deviation from the customary method should force the manipulator along an unaccustomed path, it would give the investigator an opportunity to obtain a part or the whole of the secret. Thus … it seems likely that through the study of the abnormal or unusual some insight may be obtained into that mystery of mysteries, the development of an organism … especially … where the abnormalities … are due to some modification in the germ itself, leading the organism to develop in accordance with laws as definite and natural, though not as usual, as those governing normal development (Wilder, '08). © 1992 Wiley ‐Liss, Inc.
We evaluated six pairs of conjoined twins: four pairs were dicephalus, and two were of the ischiopagus type. In three of the four dicephalus pairs, the right twin had an abnormality of laterality that included a right aortic arch, reversed great vessel orientation, bilateral right-sided isomerism of the lungs, asplenia, and situs inversus of the viscera. The left twin had normal great vessel orientation and situs solitus in each case. The finding that was unique in these three dicephalus twin pairs was their fused hearts, which were similar in orientation and configuration. The fourth dicephalus twin pair had one normally rotated heart, which was located in the midline and had normally placed chambers and great vessels. Each twin of this pair had normal visceral situs.
In the two pairs of ischiopagus twins, each pair had two separate hearts, with normal cardiac structure and great vessel relationships. The viscera expressed normal laterality. Documentation of a defect in laterality in the right twin in three conjoined twin pairs with fusion of the hearts, combined with the presence of normal laterality in three pairs without cardiac fusion, has implications regarding the mechanisms leading to laterality of the human embryo. We suggest that rotation of the heart initiates the embryo's process of lateralization and that the laterality defects of the viscera seen in the right twin are a result of their abnormal cardiac rotation.
While significant progress has been made in understanding the molecular events underlying the early specification of the antero-posterior and dorso-ventral axes, little information is available regarding the cellular or molecular basis for left-right (LR) differences in animal morphogenesis. We describe the expression patterns of three genes involved in LR determination in chick embryos: activin receptor IIa, Sonic hedgehog (Shh), and cNR-1 (related to the mouse gene nodal). These genes are expressed asymmetrically during and after gastrulation and regulate the expression of one another in a sequential pathway. Moreover, manipulation of the sidedness of either activin protein or Shh expression alters heart situs. Together, these observations identify a cascade of molecular asymmetry in that determines morphological LR asymmetry in the chick embryo.
Growth factors related to TGF-beta provide important signals for patterning the vertebrate body plan. One such family member, nodal, is required for formation of the primitive streak during mouse gastrulation. Here we have used a nodal-lacZ reporter allele to demonstrate asymmetric nodal expression in the mouse node, a structure thought to be the functional equivalent of the frog and chick 'organizer', and in lateral place mesoderm cells. We have also identified two additional genes acting with nodal in a pathway determining the left-right body axis. Thus we observe in inv mutant embryos that the sidedness of nodal expression correlates with the direction of heart looping and embryonic turning. In contrast, HNF3-beta(+/-) nodal(lacZ/+) double-heterozygous embryos display LacZ staining on both left and right sides, and frequently exhibit defects in body situs. Taken together, these experiments, along with similar findings in chick, demonstrate that elements of the genetic pathway that establish the left-right body axis are conserved in vertebrates.
The myth of rachipagus twins is hereby exploded-the myth, not the rachipagus! In a review of over 1,200 cases of conjoined twins, one classic example of rachipagus was found-two complete infants with dorsal union of the entire head and trunk, with roentgenograms showing clearly visible bony union of the vertebral arches from T6 to L3. After the typical case was discovered, 20 dorsal parasitic twins were reevaluated and reclassified as rachipagus. Two had extensive vertebral fusion and 18 were united in the dorsal midline, all with a meningocele, vertebral anomaly, and/or bony or neural connection. A theory of the embryologic origin of these twins is proposed: two embryonic discs located on diametrically opposing aspects of a single amniotic cavity becoming united in the area of the closing neural folds. This again raises the controversy concerning "fission or fusion" in conjoined twins.
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