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Retinoic Acid Controls the Bilateral Symmetry of Somite Formation in the Mouse Embryo
Abstract
A striking characteristic of vertebrate embryos is their bilaterally symmetric body plan, which is particularly obvious at the level of the somites and their derivatives such as the vertebral column. Segmentation of the presomitic mesoderm must therefore be tightly coordinated along the left and right embryonic sides. We show that mutant mice defective for retinoic acid synthesis exhibit delayed somite formation on the right side. Asymmetric somite formation correlates with a left-right desynchronization of the segmentation clock oscillations. These data implicate retinoic acid as an endogenous signal that maintains the bilateral synchrony of mesoderm segmentation, and therefore controls bilateral symmetry, in vertebrate embryos.
... These negative feedback loops are considered to generate cell-autonomous rhythms of gene expression (14)(15)(16). Cells in the PSM interact with their neighbors via Delta-Notch signaling (17)(18)(19)(20). It is thought that Her proteins repress the transcription of deltaC mRNA, causing oscillatory expression of DeltaC protein on the cell's surface (17,21). ...
... Several lines of evidence based on the desynchronization of the segmentation clock show that Delta-Notch signaling couples and thereby synchronizes neighboring genetic oscillators in the zebrafish PSM and tailbud. The first collective oscillation of the segmentation clock occurs immediately before the onset of gastrulation at 4.5 hours post fertilization (hpf), independently of Delta-Notch signaling (19,22). Thereafter, cells from embryos deficient in Delta-Notch signaling gradually become desynchronized due to the presence of various sources of noise (17,23). ...
... At the tissue level, Delta-Notch mutants form the anterior 4~6 segments normally, followed by consecutive defective segments (24). These phenotypes are not caused by a direct failure of segment boundary formation (25), but have been explained in terms of the underlying desynchronization of the segmentation clock (18,19). ...
Rhythmic spatial gene expression patterns termed the segmentation clock regulate vertebrate body axis segmentation during embryogenesis. The integrity of these patterns requires local synchronization between neighboring cells by Delta-Notch signaling and its inhibition results in defective segment boundaries. The oscillating tissue deforms substantially throughout development, but whether such tissue-scale morphogenesis complements local synchronization during pattern generation and segment formation is not understood. Here, we investigate pattern recovery in the zebrafish segmentation clock by washing out a Notch inhibitor, allowing resynchronization at different developmental stages, and analyzing the recovery of normal segments. Although from previous work no defects are expected after recovery, we find that washing out at early stages causes a distinctive intermingling of normal and defective segments, suggesting unexpectedly large fluctuations of synchrony before complete recovery. To investigate this recovery behavior, we develop a new model of the segmentation clock combining key ingredients motivated by prior experimental observations: coupling between neighboring oscillators, a frequency profile, a gradient of cell mixing, tissue length change, and cell advection pattern. This model captures the experimental observation of intermingled normal and defective segments through the formation of persistent phase vortices of the genetic oscillators. Experimentally observed recovery patterns at different developmental stages are predicted by temporal changes of tissue-level properties, such as tissue length and cell advection pattern in the model. These results suggest that segmental pattern recovery occurs at two scales: local pattern formation and transport of these patterns through tissue morphogenesis, highlighting a generic mechanism of pattern dynamics within developing tissues.
SIGNIFICANCE
Interacting genetic oscillators can generate a coherent rhythm and a tissue-level pattern from an initially desynchronized state. Using experiment and theory we study resynchronization and pattern recovery of the zebrafish segmentation clock, which makes the embryonic body segments. Experimental perturbation of intercellular signaling with an inhibitor results in intermingled normal and defective segments. According to theory, this behavior may be caused by persistent local vortices scattered in the tissue during pattern recovery. Full pattern recovery follows dynamic global properties, such as tissue length and advection pattern, in contrast to other genetic oscillators in a static tissue such as circadian clocks. Our work highlights how dynamics of tissue level properties may couple to biochemical pattern formation in tissues and developing embryos.
... Somites are 3D multicellular units, typically with an outer epithelial layer surrounded by a fibronectin-rich extracellular matrix, that form by segmentation of the presomitic mesoderm (PSM) 1,2 . The anteroposterior (AP) length of somites and their left-right symmetry is thought to be determined in the unsegmented PSM by genetic oscillations of a segmentation clock and downstream molecular prepatterns 1,2,[8][9][10][11][12] . Although mechanical processes have also been associated with somite morphogenesis 13-17 , their role in determining AP length and left-right symmetry, if any, is not understood. ...
... The AP length of somites has been historically understood from the perspective of the segmentation clock and downstream molecular processes in the PSM, and bilateral somite formation has largely been considered to be symmetric 3 . Asymmetry was thought to arise only when retinoic acid signalling was lost, exposing molecular prepatterns in the PSM to a gene expression program that determines left-sided organ positioning [10][11][12]31 . However, our findings that the initial lengths are imprecise, but are adjusted by 3D somite deformations, show that this perspective is insufficient to describe the length and symmetry of somites. ...
The body axis of vertebrate embryos is periodically segmented into bilaterally symmetric pairs of somites1,2. The anteroposterior length of somites, their position and left–right symmetry are thought to be molecularly determined before somite morphogenesis3,4. Here we show that, in zebrafish embryos, initial somite anteroposterior lengths and positions are imprecise and, consequently, many somite pairs form left–right asymmetrically. Notably, these imprecisions are not left unchecked and we find that anteroposterior lengths adjust within an hour after somite formation, thereby increasing morphological symmetry. We find that anteroposterior length adjustments result entirely from changes in somite shape without change in somite volume, with changes in anteroposterior length being compensated by corresponding changes in mediolateral length. The anteroposterior adjustment mechanism is facilitated by somite surface tension, which we show by comparing in vivo experiments and in vitro single-somite explant cultures using a mechanical model. Length adjustment is inhibited by perturbation of molecules involved in surface tension, such as integrin and fibronectin. By contrast, the adjustment mechanism is unaffected by perturbations to the segmentation clock, therefore revealing a distinct process that influences morphological segment lengths. We propose that tissue surface tension provides a general mechanism to adjust shapes and ensure precision and symmetry of tissues in developing embryos.
... It has also been suggested that retinoic acid (RA) may be involved in the wavefront. RA signalling is active in the formed somites and anterior PSM, but not in the posterior PSM, of zebrafish, frog, chick and mouse embryos (Mueller, Huang and Ho, 2010;Moreno and Kintner, 2004;Berggren et al., 1999;Vermot, 2005). This, combined with experiments showing mutual inhibition between RA and FGF signalling in the PSM of frog, chick and mouse embryos, led to the suggestion that the wavefront may be positioned by opposing gradients of RA and FGF (Moreno and Kintner, 2004;Diez del Corral et al., 2003;Abu-Abed et al., 2001). ...
... This, combined with experiments showing mutual inhibition between RA and FGF signalling in the PSM of frog, chick and mouse embryos, led to the suggestion that the wavefront may be positioned by opposing gradients of RA and FGF (Moreno and Kintner, 2004;Diez del Corral et al., 2003;Abu-Abed et al., 2001). Inhibiting RA synthesis leads to the formation of smaller somites in chick and mouse embryos (Vermot and Pourquié, 2005;Vermot, 2005), as would be predicted by a role of RA in the wavefront. However, it has been argued that RA inhibition-caused somite defects in mouse, at least, are caused by left-right symmetry defects, rather than any wavefront shift (Sirbu and Duester, 2006;Niederreither et al., 2002). ...
In vertebrate embryos, a process called somitogenesis lays the foundations of the adult spine. This process involves elongation and segmentation of the paraxial mesoderm to form somites. Although the segmentation aspect of this has been widely studied, the elongation aspect is not well understood. Posterior growth is widely assumed to be the main driver, but there is very little evidence for this – particularly in fast-developing species like zebrafish. In this thesis, I present the first long term, multi-scale, 3D characterisation of the zebrafish paraxial mesoderm, and show that this tissue elongates through some form of convergent extension, not through growth. In fact, the tissue is compressed over time, and so decreases in volume. I suggest that these processes may be functionally linked, and thus propose a novel mechanism of “compression-extension”. Cell tracking, agent-based modelling, and perturbations show that this form of convergent extension does not involve PCP-dependent directional intercalation but, instead, involves convergent flows of cells towards the midline and non-directional intercalation. The cause of compression is not clear, but perturbation experiments suggest that extrinsic forces from the neural tube and TGFβ signalling may be involved. Comparative work in cichlids, chickens, and catsharks suggests that tissue convergence is not unique to zebrafish, and instead is a conserved feature of paraxial mesoderm elongation – even in species that undergo high levels of growth during somitogenesis. This suggests that the relative contributions of growth and tissue convergence to the process of paraxial mesoderm elongation have evolved differently across vertebrate lineages, resulting in a spectrum of elongation strategies.
... When the RA ligand binds to RAR, the corepressors are replaced by a set of coactivators including histone acetyltransferases, contributing to active transcription of RA target genes 5,6 . In the absence of RA signalling in the mouse embryo, somite formation becomes asymmetrical, showing a significant delay on the right side 7 . A similar somite desynchronization phenotype is also observed in mutants for the protein Rere (or Atrophin2) which acts as a coactivator for RA signalling 8 . ...
... The molecular mechanisms controlling embryonic bilateral symmetry are still poorly understood. In mouse, the only genes shown to act in this process are Raldh2 and Rere which are involved in the control of RA signalling7,8 . Here, we identify a novel protein complex, called WHHERE which associates key epigenetic regulators such as Wdr5, Hdac1 and Hdac2 to the control of bilateral symmetry downstream of RA signalling. ...
Bilateral symmetry is a striking feature of the vertebrate body plan organization. Vertebral precursors, called somites, provide one of the best illustrations of embryonic symmetry. Maintenance of somitogenesis symmetry requires Retinoic acid (RA) and its coactivator Rere/Atrophin2. Here, using a proteomic approach we identify a protein complex, containing Wdr5, Hdac1, Hdac2 and Rere (named WHHERE), which regulates RA signalling and controls embryonic symmetry. We demonstrate that Wdr5, Hdac1 and Hdac2 are required for RA signalling in vitro and in vivo. Mouse mutants for Wdr5 and Hdac1 exhibit asymmetrical somite formation characteristic of RA-deficiency. We also identify the Rere-binding histone methyltransferase Ehmt2/G9a, as a RA coactivator controlling somite symmetry. Upon RA treatment, WHHERE and Ehmt2 become enriched at RA target genes to promote RNA Polymerase II recruitment. Our work identifies a novel protein complex linking key epigenetic regulators acting in the molecular control of embryonic bilateral symmetry.
... Previous evidence has identified that, in mouse embryos, disturbance of the retinoic acid pathway might damage the left-right bilateral symmetry, since the retinoic acid pathway controls the segmental structure of the vertebrate body plan in embryogenesis and is important in segmentation clock development [7][8][9]. Recently, it has been reported that CS, which is caused by vitamin A deficiency (VAD) during pregnancy, in postnatal rats may be induced by a retinoic acid pathway abnormality in somitogenesis [10]. ...
... Retinoic acid, the active vitamin A, plays vital roles in numerous physiological processes, such as chondrogenesis, osteochondral development, and cell differentiation [20][21][22]. Including retinoic acid signaling pathways, at least four signaling pathways have been reported to regulate the segmentation clock, such as the Notch, Fgf, and Wnt pathways [7,8,23]. ...
Background/aims:
Congenital scoliosis (CS) is a result of anomalous development of vertebrae and is frequently associated with somitogenesis malformation. Although noncoding RNAs (ncRNAs) have been recently determined to be involved in the pathogenesis of CS, the competing endogenous RNA (ceRNA) regulatory networks in CS remain largely unknown.
Methods:
Sequencing was conducted to explore the ncRNA expression profiles in rat embryos (gestation day 9) following vitamin A deficiency (VAD) (n = 9 for the vitamin A deficiency-induced congenital scoliosis (VAD-CS) group and n = 4 for the control group). Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted to verify the expression levels of selected mRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). Bioinformatics analysis was used to discover the possible relationships and functions of the ceRNAs.
Results:
A total of 749 mRNAs, 56 miRNAs, 685 lncRNAs, and 70 circRNAs were identified to have significantly different expression levels in the two groups. Wnt, PI3K-ATK, FoxO, EGFR, and mTOR were found to be the most significant pathways involved in VAD-CS pathogenesis. The circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks of CS were built, and the gene expression mechanisms regulated by ncRNAs were unveiled via the ceRNA regulatory networks.
Conclusion:
We comprehensively identified ceRNA regulatory networks of embryonic somite development in VAD-CS as well as revealed the contribution of different ncRNA expression profiles. Our data demonstrate the association between mRNAs and ncRNAs in the pathogenic mechanism of CS.
... Interestingly, besides belonging to the same family of nuclear receptors, RXR and TR often heterodimerize. Both retinoids and THs are involved in the regulation of processes such as differentiation of the cerebellum, axonal migration and myelination [317], and the control of lateralization and symmetry of the embryo [383,382]; processes that have been implicated in schizophrenia [293]. Among the genes regulated by retinoids and THs are those that encode myelin basic protein [317], dopamine receptor D2 [327] and neuregulin 1 receptor, ERBB4 [285], which have all been implicated in schizophrenia. ...
... Thyroid hormones and retinoids are essential for the normal mammalian brain development [221,268]. They regulate processes such as differentiation of the cerebellum, axonal migration and myelination [317], and the control of lateralization and symmetry of the embryo [383,382]; processes that have been implicated in schizophrenia [293]. Their mechanism of action is mainly through the regulation of transcription of genes including those encoding myelin basic protein [317], dopamine receptor D2 [327] and the receptor for neuregulin1, ERBB4 [285]; all genes previously implicated in schizophrenia. ...
... Raldh2 -/embryos, deficient in retinoic acid (RA) synthesis and signaling, display small somites and a shortened trunk due to loss of Fgf8 repression, resulting in an anterior shift in the caudal expression boundary of Fgf8 (Diez del Corral et al., 2003;Vermot et al., 2005;Sirbu and Duester, 2006;Kumar and Duester, 2014). Raldh2 -/embryos also display strong up-regulation of caudal Wnt8a that expands into the developing trunk (Zhao and Duester, 2009). ...
... RA, generated in the somites, signals to antagonize both Fgf8 and Wnt caudally (Diez del Corral et al., 2003;Vermot et al., 2005;Sirbu and Duester, 2006;Olivera-Martinez and Storey, 2007;Zhao and Duester, 2009;Kumar and Duester, 2014), thus adding an additional layer of control to body axis extension (Fig. 6). Here, we demonstrate that Wnt8a is likely a direct target of RA signaling in mouse embryos, through a RARE located 4.9 kb upstream of the transcription start site of Wnt8a that is only partially conserved in humans, perhaps due to the redundant nature of Wnt8a signaling with other Wnt ligands. ...
Vertebrate body axis extension occurs in a head-to-tail direction from a caudal progenitor zone that responds to interacting signals. Wnt/β-catenin signaling is critical for generation of paraxial mesoderm, somite formation, and maintenance of the axial stem cell pool. Body axis extension requires Wnt8a in lower vertebrates, but in mammals Wnt3a is required, although the anterior trunk develops in the absence of Wnt3a.
We examined mouse Wnt8a(-/-) and Wnt3a(-/-) single and double mutants to explore whether mammalian Wnt8a contributes to body axis extension and to determine whether a posterior growth function for Wnt8a is conserved throughout the vertebrate lineage. We find that caudal Wnt8a is expressed only during early somite stages and is required for normal development of the anterior trunk in the absence of Wnt3a. During this time, we show that Wnt8a and Wnt3a cooperate to maintain Fgf8 expression and prevent premature Sox2 upregulation in the axial stem cell niche, critical for posterior growth. Similar to Fgf8, Wnt8a requires retinoic acid (RA) signaling to establish its expression boundaries and possesses an upstream RA response element that binds RA receptors.
These findings provide new insight into interaction of caudal Wnt-FGF-RA signals required for body axis extension. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
... It has also been shown that loss of RA results in loss of bilateral symmetry of the somites since the Fgf8 signalling gradient is expressed more anteriorly and genes that are required to control the oscillation of Notch expression such as Hes7 and Lnfg are expressed asymmetrically [8][9][10]. ...
... This probably occurs because of anteriorization of the FGF8 caudal gradient. Normally fgf8 is expressed in a caudal to rostral gradient, while Raldhs are expressed in the rostral presomitic mesoderm [10,118]. It is believed that RA acts as a factor that prevents leftright asymmetry from occurring in the pre-somitic mesoderm. ...
... Thus, inhibition of P19C5 EB elongation by donepezil might occur through the suppression of Aldh1a2 expression and subsequent reduction in RA level. Reduction in RA signaling causes expansion of Fgf8 and Cdx2 expression at the posterior region (Diez del Corral et al., 2003;Vermot et al., 2005;Zhao and Duester, 2009), so suppression of Aldh1a2 expression could also be responsible for the up-regulation of Fgf8 and Cdx2 expression in donepezil-treated P19C5 EBs. Aldh1a2-null mutant embryos also exhibit impaired somitogenesis, resulting in smaller and asymmetrically organized somites (Niederreither et al., 1999;Vermot et al., 2005). ...
... Reduction in RA signaling causes expansion of Fgf8 and Cdx2 expression at the posterior region (Diez del Corral et al., 2003;Vermot et al., 2005;Zhao and Duester, 2009), so suppression of Aldh1a2 expression could also be responsible for the up-regulation of Fgf8 and Cdx2 expression in donepezil-treated P19C5 EBs. Aldh1a2-null mutant embryos also exhibit impaired somitogenesis, resulting in smaller and asymmetrically organized somites (Niederreither et al., 1999;Vermot et al., 2005). Similarly, donepezil-treated P19C5 EBs displayed marked suppression of the somitogenesis regulators Foxc2, Meox1, and Mesp2À Àwhich might be caused by the down-regulation of Aldh1a2. ...
Various compounds, including therapeutic drugs, can adversely impact the survival and development of embryos in the uterus. Identification of such development-interfering agents is a challenging task, although multi-angle approaches—including the use of in vitro toxicology studies involving embryonic stem cells—should alleviate some of the current difficulties. In the present study, we utilized the in vitro elongation of embryoid bodies (EBs) derived from mouse embryonal carcinoma stem cell line P19C5 as a model of early embryological events, specifically that of gastrulation and axial patterning. From our study, we identified donepezil, a medication indicated for the management of Alzheimer's disease, as a potential developmental toxicant. The extent of P19C5 EB axial elongation was diminished by donepezil in a dose-dependent manner. Although donepezil is a known inhibitor of acetylcholinesterase, interference of elongation was not mediated through this enzyme. Quantitative reverse-transcriptase PCR revealed that donepezil altered the expression pattern of a specific set of developmental regulator genes involved in patterning along the anterior–posterior body axis. When tested in mouse whole embryo culture, donepezil caused morphological abnormalities including impaired somitogenesis. Donepezil also diminished elongation morphogenesis of EBs generated from human embryonic stem cells. These results suggest that donepezil interferes with axial elongation morphogenesis of early embryos by altering the expression pattern of regulators of axial development. Mol. Reprod. Dev. 2014. © 2014 Wiley Periodicals, Inc.
... As well as specifying the somite boundaries, retinoic acid 20 signalling suppresses signals that break left-right symmetry, ensuring that somite production is bilaterally symmetric (J. Vermot and Pourquié 2005;Julien Vermot et al. 2005). This periodic addition of somites underlies body plan generation in all vertebrates, and the oscillating signals from Notch, Wnt and FGF pathways are conserved in the PSM of model organisms as diverse as mouse, chicken, and zebrafish (Krol et al. 2011). ...
The mammalian body plan is shaped by rhythmic segmentation of mesoderm into somites, which are transient embryonic structures consisting of hundreds of cells that form down each side of the neural tube. We have systematically analysed the genome-wide transcriptional and chromatin dynamics occurring within nascent somites, from early inception of somitogenesis to the latest stages of body plan establishment. We created matched gene expression and open chromatin maps for the three leading pairs of somites at six time points during embryonic development. Here we show that the rate of somite differentiation accelerates as development progresses. We identified a conserved maturation programme followed by all somites after segmentation, but somites from more developed embryos concomitantly switch on differentiation programmes from derivative cell lineages soon after segmentation. Integrated analysis of the somitic transcriptional and chromatin activities revealed opposing regulatory modules controlling the onset of differentiation. We identified transcription factors expressed during early development that inhibit the activity of proteins required for commitment and differentiation of skeletal cell populations. Our results provide a powerful, high-resolution view of the molecular genetics underlying somitic development in mammals.
... Similarly, three RA-signaling pathway genes have also undergone significant alteration in RFP, that is, rdh14 (REGs, P = 3.69 × 10 −3 ), rere (SCNEs) and rarb (SCNEs) (Fig. 4b, Supplementary Tables 90, 98 and 99 and Supplementary Notes 20 and 22). These genes encode core components in the RA signal pathway [95][96][97] and defects in rdh, rere or rar genes were observed to cause RA-signaling alteration, which results in multiple congenital abnormalities, including bilateral asymmetry of eyes, craniums or somites in vertebrates 97,98 . Our enzyme catalytic activity assay further lends support for such functional alterations in these RA-signaling genes. ...
... This gradient is involved in regulating the anterior reach of the FGF gradient [114]. In addition, RA is involved in regulating the left/right symmetry of somite formation in chick, mouse and Xenopus [115][116][117]. Canonical Wnt signaling is mediated by signaling activity of -catenin, which is also involved in cell-cell adhesion on cell membranes. ...
Developmental patterning shows remarkable robustness in the face of changing environmental conditions. One particular challenge faced by externally fertilized embryos is how to maintain proper growth and patterning despite temperature variation. In order to address the mechanism behind temperature-invariant patterning, I study somitogenesis in Japanese medaka (Oryzias latipes), which has been shown to tolerate a wide range of temperatures. The periodic formation of somites from the presomitic mesoderm (PSM) in vertebrates is under the control of a molecular “clock”, consisting of oscillatory target genes in the Notch, Wnt and FGF signaling pathways. While it is clear that these periodic signals are involved in regulating the timing of somitogenesis, how oscillations encode information, and how this is coordinated in space is still a matter of ongoing research. To study somitogenesis in medaka, I generated endogenous knock-in reporters to visualize signaling activity in the Notch, Wnt and FGF pathways during somite formation. Importantly, an oscillating Notch signaling reporter, Her7-Venus, allows quantification of segmentation clock oscillations in medaka for the first time. Time-lapse imaging of Her7-Venus oscillations revealed coherent waves that follow a period gradient in the PSM, which is reminiscent of dynamics in higher vertebrates. Imaging of this reporter at different temperatures revealed that segmentation clock oscillations are globally faster at higher temperatures. Importantly, while period changes 2.2 fold, average somite size changes 1.15 fold between 23-35°C. A detailed analysis of the period gradient reveals that oscillations change their period differently in the posterior and anterior PSM, resulting in a constant period gradient amplitude. In addition, the phase gradient amplitude is temperature-invariant. These results provide the first quantitative insight into how underlying signaling dynamics respond to temperature changes and allow robust patterning during somitogenesis. Examining these findings in the context of existing models of somitogenesis could provide insight into how robustness is achieved in this complex system.
... Similarly, three RA-signaling pathway genes have also undergone significant alteration in RFP, that is, rdh14 (REGs, P = 3.69 × 10 −3 ), rere (SCNEs) and rarb (SCNEs) (Fig. 4b, Supplementary Tables 90, 98 and 99 and Supplementary Notes 20 and 22). These genes encode core components in the RA signal pathway [95][96][97] and defects in rdh, rere or rar genes were observed to cause RA-signaling alteration, which results in multiple congenital abnormalities, including bilateral asymmetry of eyes, craniums or somites in vertebrates 97,98 . Our enzyme catalytic activity assay further lends support for such functional alterations in these RA-signaling genes. ...
The evolutionary and genetic origins of the specialized body plan of flatfish are largely unclear. We analyzed the genomes of 11 flatfish species representing 9 of the 14 Pleuronectiforme families and conclude that Pleuronectoidei and Psettodoidei do not form a monophyletic group, suggesting independent origins from different percoid ancestors. Genomic and transcriptomic data indicate that genes related to WNT and retinoic acid pathways, hampered musculature and reduced lipids might have functioned in the evolution of the specialized body plan of Pleuronectoidei. Evolution of Psettodoidei involved similar but not identical genes. Our work provides valuable resources and insights for understanding the genetic origins of the unusual body plan of flatfishes.
... Raldh2 knockout mice indicated this enzyme is responsible for all RA production during early embryogenesis, until E9.0 when RALDH3 begins its expression in the forebrain [248]. Its absence affects many developing systems such as forebrain, hindbrain, heart, forelimbs and somites [248,252,[266][267][268][269][270][271], sites also affected by dietary VAD [272], or aldehyde dehydrogenase inhibitors in rodent and other species [246,273]. RALDH3 has different functions at later stages of eye and nasal development [261]. ...
The goal of this thesis is to investigate genetic and environmental factors, both initiating and influencing signaling centers that regulate tooth development and thus producing associated defects. Essentially, my research program utilizes patient-based rare disease phenotypes to create novel mouse models. This study also involved investigating the developmental effects of excess retinoic acid on enamel formation to gain understanding of the mechanisms by which environmental factors can alter enamel development. Other studies investigated enamel and dental anomalies in Ltbp3 and Smoc2 mutant mice. These results advance our understanding of tooth development, and may translate towards optimizing clinical diagnosis, and improving treatment strategies for several human rare diseases. An improved understanding of rare disease models and our testing of clinically relevant approaches using rodent models is a feasible approach to address bone degeneration problems.
... A similar set of malformations has been observed in the zebrafish raldh2 mutant liminated from the cell. Adapted from Niederreither and Dolle 2008 ADDIN EN.CITE <EndNote><C ite><Author>Niederreither</Authootype such that embryos survive until E13.5-14.5 [58][59][60][61][62][63][64][65][66][67]. 'RArescued' Raldh2 null mouse embryos and hypomorphic null allele of Raldh2 display similar phenotypes including with early abnormalities of PAA1-3 and disorganized migration of the neural crest and later characteristic heart and thymus malformations similar to those described for 22q11DS and Tbx1 mutations [64,68,69]. ...
This review focuses on the role of the Cytochrome p450 subfamily 26 (CYP26) retinoic acid (RA) degrading enzymes during development and regeneration. Cyp26 enzymes, along with retinoic acid synthesising enzymes, are absolutely required for RA homeostasis in these processes by regulating availability of RA for receptor binding and signalling. Cyp26 enzymes are necessary to generate RA gradients and to protect specific tissues from RA signalling. Disruption of RA homeostasis leads to a wide variety of embryonic defects affecting many tissues. Here, the function of CYP26 enzymes is discussed in the context of the RA signalling pathway, enzymatic structure and biochemistry, human genetic disease, and function in development and regeneration as elucidated from animal model studies.
... In this connection, it has been reported that somite development requires a molecular oscillator, which is known as the segmentation clock (Li et al. 2012;Vilhais-Neto et al. 2010). It regulates rhythmic expression of the cyclic genes (Vermot et al. 2005). Somites can differentiate into ribs, intercostal, vertebrae, skeletal muscles, and tendons of body (Pickett et al. 2008;Sweetman et al. 2006;Zhang et al. 2011). ...
Circular RNAs (circRNAs) are an important class of non-coding RNAs partly by acting as microRNA sponges. Growing evidence indicates that air pollution exposure during pregnancy could lead to congenital defects in the offspring. In this study, using circRNAs sequencing, we profiled differentially expressed circRNAs in rat embryos exposed to a high concentration (> 200 μg/m³) of fine particulate matter (PM2.5) in utero. Compared with the control embryos whose mothers were reared in clean air, 25 and 55 circRNAs were found to be downregulated and upregulated, respectively, in the air pollution–exposed group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of circRNA-coexpressed genes indicated that segmentation, brain development, and system development together with lysine degradation, Rap1 signaling pathway, and adrenergic signaling were deregulated by in utero air pollution exposure. We also identified the central role of three circRNAs, namely circ_015003, circ_030724, and circ_127215 in the circRNA-microRNA interaction network. These data suggested that circRNA deregulation might play a crucial role in the development of air pollution–associated congenital malformations.
... possibly because RAs control the development of the segmental structure of the vertebrate body during embryogenesis. [8][9][10] Retinoic acid is a metabolite of vitamin A (retinol) that mediates the critical functions of vitamin A in growth and development. However, the mechanisms underlying VAD-induced CS remain unclear. ...
Congenital scoliosis (CS) is the result of anomalous vertebrae development, but the pathogenesis of CS remains unclear. Long non‐coding RNAs (lncRNAs) have been implicated in embryo development, but their role in CS remains unknown. In this study, we investigated the role and mechanisms of a specific lncRNA, SULT1C2A, in somitogenesis in a rat model of vitamin A deficiency (VAD)‐induced CS. Bioinformatics analysis and quantitative real‐time PCR (qRT‐PCR) indicated that SULT1C2A expression was down‐regulated in VAD group, accompanied by increased expression of rno‐miR‐466c‐5p but decreased expression of Foxo4 and somitogenesis‐related genes such as Pax1, Nkx3‐2 and Sox9 on gestational day (GD) 9. Luciferase reporter and small interfering RNA (siRNA) assays showed that SULT1C2A functioned as a competing endogenous RNA to inhibit rno‐miR‐466c‐5p expression by direct binding, and rno‐miR‐466c‐5p inhibited Foxo4 expression by binding to its 3′ untranslated region (UTR). The spatiotemporal expression of SULT1C2A, rno‐miR‐466c‐5p and Foxo4 axis was dynamically altered on GDs 3, 8, 11, 15 and 21 as detected by qRT‐PCR and northern blot analyses, with parallel changes in Protein kinase B (AKT) phosphorylation and PI3K expression. Taken together, our findings indicate that SULT1C2A enhanced Foxo4 expression by negatively modulating rno‐miR‐466c‐5p expression via the PI3K‐ATK signalling pathway in the rat model of VAD‐CS. Thus, SULT1C2A may be a potential target for treating CS.
... Retinoic acid, which is the metabolite of vitamin A, plays important roles in several developmental processes, including osteochondral differentiation and chondrogenesis. 42,43 To date, at least four signaling pathways, namely Notch, retinoic acid, Wnt and Fgf cascades, are known to modulate the segmentation clock. 44 However, the precise regulation of these signaling pathways remains unknown. ...
Congenital spinal deformities are a result of defective somitogenesis and are associated with vitamin A deficiency (VAD). However, the molecular mechanisms of VAD‐associated congenital spinal deformities remain largely unknown. Increasing number of studies suggested that microRNAs and melatonin played important roles in the developemnt of congenital spinal deformities. In this study, we showed that the whole‐embryo expression of miR‐363 was upregulated in VAD rats. Furthermore, we demonstrated that miR‐363 inhibited the proliferation and neuronal differentiation of primary cultured NSCs, accompanied by downregulation of Notch1. To this end, melatonin suppressed miR‐363 expression and rescued the effects of miR‐363 on NSC proliferation and neuronal differentiation together with restoration of Notch signaling. The present study provided new insights into the mechanism of VAD‐associated spinal deformities and the therapeutic effect of melatonin that may lead to novel understanding of the molecular mechanisms of congenital spinal deformities.
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... The results of this study were in accordance with these findings. Deficient signalling in mice leads to delayed somite formation on the right side, causing a diminished coordination between the development of the left and right somites, and leading to a differential expression of the Hox genes (Griesinger et al. 2005;Vermot et al. 2005). ...
The number of cervical vertebrae in mammals is almost constant at seven, regardless of their neck length, implying that there is selection against variation in this number. Homebox (Hox) genes are involved in this evolutionary mammalian conservation, and homeotic transformation of cervical into thoracic vertebrae (cervical ribs) is a common phenotypic abnormality when Hox gene expression is altered. This relatively benign phenotypic change can be associated with fatal traits in humans. Mutations in genes upstream of Hox, inbreeding and stressors during organogenesis can also cause cervical ribs. The aim of this study was to describe the prevalence of cervical ribs in a large group of domestic dogs of different breeds, and explore a possible relation with other congenital vertebral malformations (CVMs) in the breed with the highest prevalence of cervical ribs. By phenotyping we hoped to give clues as to the underlying genetic causes. Twenty computed tomography studies from at least two breeds belonging to each of the nine groups recognized by the Federation Cynologique Internationale, including all the brachycephalic 'screw-tailed' breeds that are known to be overrepresented for CVMs, were reviewed. The Pug dog was more affected by cervical ribs than any other breed (46%; P < 0.001), and was selected for further analysis. No association was found between the presence of cervical ribs and vertebral body formation defect, bifid spinous process, caudal articular process hypoplasia/ aplasia and an abnormal sacrum, which may infer they have a different aetiopathogenesis. However, Pug dogs with cervical ribs were more likely to have a transitional thoraco-lumbar vertebra (P = 0.041) and a pre-sacral vertebral count of 26 (P < 0.001). Higher C7/T1 dorsal spinous processes ratios were associated with the presence of cervical ribs (P < 0.001), supporting this is a true homeotic transformation. Relaxation of the stabilizing selection has likely occurred, and the Pug dog appears to be a good naturally occurring model to further investigate the aetiology of cervical ribs, other congenital vertebral anomalies and numerical alterations.
... Retinoic acid (RA), the active metabolite of Vitamin A, is an essential molecule required for vertebrate development and tissue homeostasis [12][13][14][15] . RA binds to nuclear receptors and regulates numerous biological processes including cellular differentiation, adhesion, migration, and tissue remodeling [16][17][18][19] . ...
In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment
plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion.
However, the nature of the stromal cells and molecular pathways involved remain largely
unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid
acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in
stromal cells causes deregulation of genes associated with adhesion, tissue organization and
chemokine secretion including the B-cell chemokine CXCL13. Notably, reducing retinoic acid
precursors from the diet or inhibiting RA-signaling through retinoid-antagonist therapy
prolong survival by preventing dissemination of leukemia cells into lymphoid tissues. These findings establish a role for
retinoids in murine CLL pathogenesis, and provide new therapeutic strategies to target the
microenvironment and to control disease progression.
... RA distribution in the body is highly regulated by retinol availability and tissue/cell-specific expression of RA-synthesizing and catabolizing enzymes. During embryo development, RA gradients serve as major morphogens to regulate organ development (16,17). ATRA is produced by cells that express alcohol dehydrogenases (ADHs) and retinal dehydrogenases (RALDH1-3) that metabolize retinol. ...
Lymphocytes, such as T cells, B cells, and innate lymphoid cells (ILCs), play central roles in regulating immune responses. Retinoic acids (RAs) are vitamin A metabolites, produced and metabolized by certain tissue cells and myeloid cells in a tissue-specific manner. It has been established that RAs induce gut-homing receptors on T cells, B cells, and ILCs. A mounting body of evidence indicates that RAs exert far-reaching effects on functional differentiation and fate of these lymphocytes. For example, RAs promote effector T cell maintenance, generation of induced gut-homing regulatory and effector T cell subsets, antibody production by B cells, and functional maturation of ILCs. Key functions of RAs in regulating major groups of innate and adaptive lymphocytes are highlighted in this article.
... When the RA ligand binds to RAR, the corepressors are replaced by a set of coactivators including histone acetyltransferases, contributing to active transcription of RA target genes 5,6 . In the absence of RA signaling in the mouse embryo, somite formation becomes asymmetrical, showing a significant delay on the right side 7 . A similar somite desynchronization phenotype is also observed in mutants for the protein Rere (or Atrophin2) which acts as a coactivator for RA signalling 8 . ...
Bilateral symmetry is a striking feature of the vertebrate body plan organization. Vertebral precursors, called somites, provide one of the best illustrations of embryonic symmetry. Maintenance of somitogenesis symmetry requires retinoic acid (RA) and its coactivator Rere/Atrophin2. Here, using a proteomic approach we identify a protein complex, containing Wdr5, Hdac1, Hdac2 and Rere (named WHHERE), which regulates RA signaling and controls embryonic symmetry. We demonstrate that Wdr5, Hdac1, and Hdac2 are required for RA signaling in vitro and in vivo. Mouse mutants for Wdr5 and Hdac1 exhibit asymmetrical somite formation characteristic of RA-deficiency. We also identify the Rere-binding histone methyltransferase Ehmt2/G9a, as a RA coactivator controlling somite symmetry. Upon RA treatment, WHHERE and Ehmt2 become enriched at RA target genes to promote RNA polymerase II recruitment. Our work identifies a protein complex linking key epigenetic regulators acting in the molecular control of embryonic bilateral symmetry.
... In Raldh2 (Aldh1a2) null mutant mice, which are defective for retinoic acid production, Papc expression was restricted to the anterior-most PSM and formed narrow asymmetrical stripes (Fig. 2P,Q; n=5). As Raldh2 mutants exhibit a FGF signaling gain-of-function phenotype in the PSM (Vermot et al., 2005), the lack of posterior expression of PAPC in these mutants is consistent with the FGFdependent repression observed in chicken embryos. Thus, our data identifies PAPC as a novel type of cyclic gene exhibiting an unusual periodic repression in the PSM downstream of FGF signaling in the mouse and chicken embryos. ...
Abstract
Vertebrate segmentation is characterized by the periodic formation of epithelial somites from the mesenchymal presomitic mesoderm (PSM). How the rhythmic signaling pulse delivered by the segmentation clock is translated into the periodic morphogenesis of somites remains poorly understood. Here, we focused on the role of paraxial protocadherin (PAPC/Pcdh8) in this process. We showed that in chicken and mouse embryos, PAPC expression is tightly regulated by the clock and wavefront system in the posterior PSM. We observed that PAPC exhibits a striking complementary pattern to N-cadherin (CDH2), marking the interface of the future somite boundary in the anterior PSM. Gain and loss of function of PAPC in chicken embryos disrupted somite segmentation by altering the CDH2-dependent epithelialization of PSM cells. Our data suggest that clathrin-mediated endocytosis is increased in PAPC-expressing cells, subsequently affecting CDH2 internalization in the anterior compartment of the future somite. This in turn generates a differential adhesion interface, allowing formation of the acellular fissure that defines the somite boundary. Thus, periodic expression of PAPC in the anterior PSM triggers rhythmic endocytosis of CDH2, allowing for segmental de-adhesion and individualization of somites.
... Differential RA signalling activities have been implicated as a key regulator of region-specific phenotypes. For example, RALDH2 À / À mouse embryos have been reported to show bilaterally asymmetric somitogenesis due to left-right desynchronization of segmentation clock oscillations 32 . Previous analyses of naked neck chickens revealed elevated RA in the neck potentiates BMP signalling, which inhibits feather formation 33 . ...
Adaptation of feathered dinosaurs and Mesozoic birds to new ecological niches was potentiated by rapid diversification of feather vane shapes. The molecular mechanism driving this spectacular process remains unclear. Here, through morphology analysis, transcriptome profiling, functional perturbations and mathematical simulations, we find that mesenchyme-derived GDF10 and GREM1 are major controllers for the topologies of rachidial and barb generative zones (setting vane boundaries), respectively, by tuning the periodic-branching programme of epithelial progenitors. Their interactions with the anterior–posterior WNT gradient establish the bilateral-symmetric vane configuration. Additionally, combinatory effects of CYP26B1, CRABP1 and RALDH3 establish dynamic retinoic acid (RA) landscapes in feather mesenchyme, which modulate GREM1 expression and epithelial cell shapes. Incremental changes of RA gradient slopes establish a continuum of asymmetric flight feathers along the wing, while switch-like modulation of RA signalling confers distinct vane shapes between feather tracts. Therefore, the co-option of anisotropic signalling modules introduced new dimensions of feather shape diversification.
... Other bilaterally symmetric structures in the embryo, such as the somites, also need to override the influence of early asymmetric gene expression associated with the L/R pathway. RA signalling is essential to synchronize somite formation between left and right sides by antagonizing Fgf8 to ensure symmetric FGF signalling activity on the both sides of embryos [26][27][28]. Together with our study, these results suggest that buffering the effects of the left-right pathways is a general strategy employed during the formation of bilaterally symmetric structures in the developing embryo. Significantly, however, the mechanisms by which bilateral symmetry is achieved are different in different structures, such as the limbs and somites. ...
Author Summary
Externally, the human form appears bilaterally symmetric. For example, each of our pairs of arms and legs are the same length. This external symmetry masks many asymmetries found in internal organs. In most people the heart is found on the left side of the chest. The stomach, liver and spleen are also positioned asymmetrically. The authors of this study demonstrate, using a mouse model, that bilateral symmetry of the arms is not a default, passive state but that mechanisms are in place that ensure symmetrical formation of the left and right limbs. Bilateral symmetry of the arms is achieved by the action of a gene Tbx5 that masks the effects of signals that acted earlier during embryogenesis, many days before limb formation, and imposed asymmetries on the forming internal organs. Maintaining bilateral symmetry of the arms is important for them to carry out their normal functions but this process can go wrong. Holt-Oram syndrome patients have upper limb defects, including shortened arms. Consistently the defects are more severe in their left arm than right. This birth defect is caused by disruption of the TBX5 gene. By linking the action of Tbx5 to symmetrical limb formation, the authors provide an explanation for why Holt-Oram syndrome patients have more severe defects in the left arms than right.
... In the Raldh2 null mutant mice which are defective for retinoic acid production, PAPC expression was restricted to the anterior-most PSM and formed narrow asymmetrical stripes (Fig. 2P, Q; n=5). As Raldh2 mutants exhibit a FGF signaling gain-of-function phenotype in the PSM (Vermot et al., 2005), the lack of posterior expression of PAPC in these mutants is . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. ...
Vertebrate segmentation is characterized by the periodic formation of epithelial
somites from the mesenchymal presomitic mesoderm (PSM). How the rhythmic
signaling pulse delivered by the Segmentation Clock is translated into the
periodic morphogenesis of somites remains poorly understood. Here, we focused
on the role of Paraxial protocadherin (PAPC/Pcdh8) in this process. We show that
in chicken and mouse embryos, PAPC expression is tightly regulated by the Clock
and Wavefront system in the posterior PSM. We observed that PAPC exhibits a
striking complementary pattern to N-Cadherin (CDH2), marking the interface of the
future somite boundary in the anterior PSM. Gain and loss of function of PAPC in
chicken embryos disrupt somite segmentation by altering the CDH2-dependent
epithelialization of PSM cells. Our data suggest that clathrin-mediated
endocytosis is increased in PAPC expressing cells, subsequently affecting CDH2
internalization in the anterior compartment of the future somite. This in turn
generates a differential adhesion interface, allowing formation of the acellular
fissure that defines the somite boundary. Thus periodic expression of PAPC
downstream of the Segmentation Clock triggers rhythmic endocytosis of CDH2,
allowing for segmental de-adhesion and individualization of somites.
... RA, the active metabolite of vitamin A, is an essential molecule required for vertebrate patterning and embryogenesis (15,26,(28)(29)(30)(31). RA binds to nuclear receptors (RARs) and regulates critical developmental pathways governing cellular proliferation, differentiation, organogenesis, and tissue homeostasis (32,33). ...
The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia.
... In addition from its ability to rescue the effect of SHH deprivation during somitogenesis [10]. RA deficient mouse or zebrafish embryos present asymmetric hes/her expression and somitogenesis [111,112], further suggesting a role for RA in this process. In the developing limb, RA has a positive influence on HES gene expression [113,114] by being a short-term, transient instructive as well as permissive signal through Erk/Akt activation and Gli3 modulation, respectively [114]. ...
Various ultradian rhythms ensure proper temporal regulations during embryo development. The embryo molecular clock, which was first identified in the presomitic mesoderm (PSM) underlying periodic somite formation, is one among them. Somites are the earliest manifestation of the segmented vertebrate body and they are formed with strict temporal precision. The tetrapod limb is also a segmented structure and the formation of limb bone elements have also been associated with a molecular clock, operating in the distal limb mesenchyme. In both the PSM and the distal limb mesenchyme, the molecular clock (MC) is influenced by FGF, SHH and RA, which are also the key regulators of the development of these tissues. While somitogenesis has been continuously scrutinized to understand the mechanisms of the MC, the limb bud has served as an outstanding paradigm to study how a cohort of undifferentiated cells is organized into functional 3D structures. The fact that both the trunk and limb development are shaped by the MC and by common signaling molecules has prompted the exciting possibility of establishing parallelisms between somitogenesis and limb development. Systematically correlating various parameters during trunk and limb development will help us to appreciate the common principles underlying segmented structure formation and allow the rise of new questions in order to fill the gaps in our present understanding. In this review we have established the parallelisms between somitogenesis and limb development at the level of gene expression patterns and their regulation. Finally, we have also discussed the most evident new avenues this exercise could open to the scientific community.
... The RA signaling is not detected in the forebrain neuroectoderm of the open neural tube at E8.5. The signaling in the somites and spinal cord reflects local RA production by the somites (Stavridis et al., 2010;Vermot et al., 2005). At E10.5, RA signaling activity in the forebrain and head is modest, confined to the ventro-lateral forebrain, eye, and nose, all reflecting local neural crest mesenchyme sources of RA (Haskell and LaMantia, 2005;LaMantia et al., 1993). ...
After neural tube closure, amniotic fluid (AF) captured inside the neural tube forms the nascent cerebrospinal fluid (CSF). Neuroepithelial stem cells contact CSF-filled ventricles, proliferate, and differentiate to form the mammalian brain, while neurogenic placodes, which generate cranial sensory neurons, remain in contact with the AF. Using in vivo ultrasound imaging, we quantified the expansion of the embryonic ventricular-CSF space from its inception. We developed tools to obtain pure AF and nascent CSF, before and after neural tube closure, and to define how the AF and CSF proteomes diverge during mouse development. Using embryonic neural explants, we demonstrate that age-matched fluids promote Sox2-positive neurogenic identity in developing forebrain and olfactory epithelia. Nascent CSF also stimulates SOX2-positive self-renewal of forebrain progenitor cells, some of which is attributable to LIFR signaling. Our Resource should facilitate the investigation of fluid-tissue interactions during this highly vulnerable stage of early brain development.
... For example, the caudal Wnt3a expression domain is expanded anteriorly in Aldh1a2-knockout embryos (Zhao and Duester, 2009), whereas Wnt3a expression was largely unaffected in EBs up until Day 2 and even down-regulated after Day 3 by BMS493 treatmentÀ Àalthough the WNT3A target gene Msgn1 was up-regulated at Day 2 ( Fig. 5C; Table S3). Furthermore, the expression of Fgf8 and its target gene Spry2 is expanded in Aldh1a2-knockout embryos (Vermot et al., 2005;Zhao and Duester, 2009;Kumar and Duester, 2014), whereas Fgf8 and Spry2 were respectively, downregulated and largely unaffected in BMS493-treated EBs (Fig. 5C). These apparent inconsistencies between the in vivo and in vitro situations are discussed below (see Discussion). ...
Certain chemical agents act as teratogens, causing birth defects and fetal deaths when pregnant women are exposed to them. The establishment of in vitro models that recapitulate crucial embryonic events is therefore vital to facilitate screening of potential teratogens. Previously, we created a three-dimensional culture method for mouse P19C5 embryonal carcinoma stem cells that, when cultured as embryoid bodies, display elongation morphogenesis resembling gastrulation, which is the critical event resulting in the germ layers and major body axes. Determination of how well this in vitro morphogenesis represents in vivo gastrulation is essential to assess its applicability as well as to identify limitations of the model for detecting teratogenic agents. Here, we investigated the morphological and molecular characteristics of P19C5 morphogenesis using pharmacological agents that are known to cause abnormal patterning in the embryo in vivo by inhibiting major developmental signaling - e.g. involving Wnt, Nodal, Bone morphogenic protein (Bmp), Fibroblast growth factor (Fgf), Retinoic acid, Notch, and Hedgehog pathways. Inhibitors of Wnt, Nodal, Bmp, Fgf, and Retinoic acid signaling caused distinct changes in P19C5 morphogenesis that were quantifiable using morphometric parameters. These five inhibitors, plus the Notch inhibitor, also altered temporal expression profiles of developmental regulator genes in a manner consistent with the in vivo roles of the corresponding signaling pathways. In contrast, the Hedgehog inhibitor did not have any impact on the process, suggesting an absence of active Hedgehog signaling in these embryoid bodies. These results indicate that the P19C5 in vitro gastrulation model is a promising tool to screen for teratogenic agents that interfere with many of the key developmental signals. This article is protected by copyright. All rights reserved.
... This indicates that NDR kinases are part of the mechanism by which somites normally escape the already existing left-right asymmetry along the primary embryonic axis [36, 50]. Possibly NDR kinases play a role in the conserved 'clock-and-wavefront' mechanism controlling somitogen- esis [51] and/or also contribute to the retinoic acid-mediated coordination of somitogenesis and left-right patterning [52][53][54][55]. Therefore, future research into the underlying molecular and cellular mechanisms is warranted. ...
Studies of mammalian tissue culture cells indicate that the conserved and distinct NDR iso-forms, NDR1 and NDR2, play essential cell biological roles. However, mice lacking either Ndr1 or Ndr2 alone develop normally. Here, we studied the physiological consequences of inactivating both NDR1 and NDR2 in mice, showing that the lack of both Ndr1/Ndr2 (called Ndr1/2-double null mutants) causes embryonic lethality. In support of compensatory roles for NDR1 and NDR2, total protein and activating phosphorylation levels of the remaining NDR isoform were elevated in mice lacking either Ndr1 or Ndr2. Mice retaining one single wild-type Ndr allele were viable and fertile. Ndr1/2-double null embryos displayed multiple phenotypes causing a developmental delay from embryonic day E8.5 onwards. While NDR kinases are not required for notochord formation, the somites of Ndr1/2-double null embryos were smaller, irregularly shaped and unevenly spaced along the anterior-posterior axis. Genes implicated in somitogenesis were down-regulated and the normally symmetric expression of Lunatic fringe, a component of the Notch pathway, showed a left-right bias in the last forming somite in 50% of all Ndr1/2-double null embryos. In addition, Ndr1/2-double null embryos developed a heart defect that manifests itself as pericardial edemas, obstructed heart tubes and arrest of cardiac looping. The resulting cardiac insufficiency is the likely cause of the lethality of Ndr1/2-double null embryos around E10. Taken together, we show that NDR kinases compensate for each other in vivo in mouse embryos, explaining why mice deficient for either Ndr1 or Ndr2 are viable. Ndr1/2-double null embryos show defects in somitogenesis and cardiac looping, which reveals their essential functions and shows that the NDR kinases are critically required during the early phase of organogenesis.
... The offset arrangement of somites regulated by Nodal signaling is specific to amphioxus development; however, the asymmetrical arrangement itself may also represent a basis for vertebrate somitogenesis. Previous experiments showed that depletion of retinoic acid in the zebrafish, chick, or mouse causes temporal acceleration of somite development on the left side [126][127][128], a situation reminiscent of normal development in amphioxus. Blum et al. [1] therefore proposed that retinoic acid signaling may act to shield vertebrate somites from Nodal signaling, which, in turn, may explain the vertebrate-specific transfer of the Nodal signal from the LR organizer to the lateral plate mesoderm without affecting the somites. ...
Nodal is an important determinant of the left-right (LR) body axis in bilaterians, specifying the right side in protostomes and non-chordate deuterostomes as opposed to the left side in chordates. Amphioxus represents an early-branching chordate group, rendering it especially useful for studying the character states that predate the origin of vertebrates. However, its anatomy, involving offset arrangement of axial structures, marked asymmetry of the oropharyngeal region, and, most notably, a mouth positioned on the left side, contrasts with the symmetric arrangement of the corresponding regions in other chordates.
We show that the Nodal signaling pathway acts to specify the LR axis in the cephalochordate amphioxus in a similar way as in vertebrates. At early neurula stages, Nodal switches from initial bilateral to the left-sided expression and subsequently specifies the left embryonic side. Perturbation of Nodal signaling with small chemical inhibitors (SB505124 and SB431542) alters expression of other members of the pathway and of left/right-sided, organ-specific genes. Upon inhibition, larvae display loss of the innate alternation of both somites and axons of peripheral nerves and loss of left-sided pharyngeal structures, such as the mouth, the preoral pit, and the duct of the club-shaped gland. Concomitantly, the left side displays ectopic expression of otherwise right-sided genes, and the larvae exhibit bilaterally symmetrical morphology, with duplicated endostyle and club-shaped gland structures.
We demonstrate that Nodal signaling is necessary for establishing the LR embryonic axis and for developing profound asymmetry in amphioxus. Our data suggest that initial symmetry breaking in amphioxus and propagation of the pathway on the left side correspond with the situation in vertebrates. However, the organs that become targets of the pathway differ between amphioxus and vertebrates, which may explain the pronounced asymmetry of its oropharyngeal and axial structures and the left-sided position of the mouth.
... 17,18 Moreover, recent studies showed that RA played a significant role in the development of somites in mouse, chick, or zebrafish embryos. [19][20][21] In addition, our previous study also demonstrated that deficiency of vitamin A during pregnancy might result in congenital spinal deformities in the postnatal rats, which was caused by a defect in RA signaling pathway during somitogenesis. 22 An interstitial 17p11.2 ...
The Smith–Magenis syndrome (SMS) is a complex and rare congenital condition that is characterized by minor craniofacial anomalies, short stature, sleep disturbances, behavioral, and neurocognitive abnormalities, as well as variable multisystemic manifestations. Little is reported about spinal deformity associated with this syndrome.
This study is to present a case of scoliosis occurring in the setting of SMS and explore the possible mechanisms between the 2 diseases.
The patient is a 13-year-old Chinese female with congenital scoliosis and Tetralogy of Fallot, mental retardation, obstructive sleep apnea, hypertrophy of tonsil, conductive hearing loss, and agenesis of the epiglottis. An interphase fluorescent in situ hybridization at chromosome 17p11.2 revealed a heterozygous deletion, confirming a molecular diagnosis of SMS. She underwent a posterior correction at thoracic 1-lumbar 1 (T1-L1) levels, using the Moss-SI spinal system. At 6-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of correction.
Congenital cardiac disease, immunodeficiency, and severe behavioral problems can affect the surgical outcome following spine fusion and need to be taken into consideration for the surgeon and anesthesiologist. Scoliosis is not uncommon among patients with SMS, and there is a potential association between congenital scoliosis and SMS. The potential mechanisms in the pathogenesis of congenital scoliosis of SMS included retinoic acid-induced 1 (RAI1) microdeletion and RAI1 gene point mutation.
... 52 With the help of high speed video imaging and blood flow pattern analysis, Vermot et al. demonstrated recently the requirement of reverse blood flow in patterning the atrioventricular valve in addition to the identification of endothelium-derived klf2a acting as a sensor of hemodynamic force and possibly as an indicator of defective valve formation. 56 Blood flow also has its impact on cardiac trabeculation, myocyte growth and chamber maturation, most likely via the endocardium. 57 -59 In the mature heart two valves are present, the atrioventricular (AV) and the bulboventricular (BV) valves ( Fig. 1). ...
... Whereas internal organs such as the heart or gut are clearly asymmetrical, somites exhibit a striking bilateral symmetry in amniote embryos. Retinoic acid has an important role in the control of the bilateral symmetry of oscillations and segmentation that leads to the formation of symmetrical somites 25,96,97,102,103,104 . In chicken, mouse or fish embryos deprived of retinoic acid, somitogenesis becomes asymmetrical between the left and right side, with somite formation being consistently delayed on one side. ...
Segmentation of the paraxial mesoderm is a major event of vertebrate development that establishes the metameric patterning of the body axis. This process involves the periodic formation of sequential units, termed somites, from the presomitic mesoderm. Somite formation relies on a molecular oscillator, the segmentation clock, which controls the rhythmic activation of several signalling pathways and leads to the oscillatory expression of a subset of genes in the presomitic mesoderm. The response to the periodic signal of the clock, leading to the establishment of the segmental pre-pattern, is gated by a system of travelling signalling gradients, often referred to as the wavefront. Recent studies have advanced our understanding of the molecular mechanisms involved in the generation of oscillations and how they interact and are coordinated to activate the segmental gene expression programme.
The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms, but remains largely elusive in humans due to ethical and technical limitations. Despite recent advances with pluripotent stem cell (PSC)-based approaches1-5, models that robustly recapitulate human somitogenesis in both space and time are still largely missing. Here, we introduce a PSC-derived mesoderm-based 3D model of human segmentation and somitogenesis, which we termed ‘axioloid’, that captures accurately the oscillatory dynamics of the segmentation clock and the morphological and molecular characteristics of sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior-posterior FGF/WNT signaling gradients and retinoic acid (RA) signaling components. We identify an unexpected critical role of RA signaling in the stabilization of forming segments, indicating distinct, but also synergistic effects of RA and extracellular matrix (ECM) on the formation and epithelialization of somites. Importantly, comparative analysis demonstrates striking similarities of axioloids to the human embryo, further validated by the presence of a HOX code in axioloids. Lastly, we demonstrate the utility of axioloids to study the pathogenesis of human congenital spine diseases, by using patient-like iPSCs with mutations in HES7 and MESP2. These results suggest that axioloids represent a promising novel platform to study axial development and disease in humans.
In recent decades, biologist have focused on the spatiotemporal regulation and function of genes to understand embryogenesis. It is clear that maternal diet impacts fetal development but how nutrients, like lipids and vitamins, modify developmental programs is not completely understood. Fish are useful research organisms for such investigations. Most species of fish produce eggs that develop outside the mother, dependent on a finite amount of yolk to form and grow. The developing embryo is a closed system that can be readily biochemically analyzed, easily visualized, and manipulated to understand the role of nutrients in tissue specification, organogenesis, and growth. Natural variation in yolk composition observed across fish species may be related to unique developmental strategies. In this review, we discuss the reasons that teleost fishes are powerful models to understand nutritional control of development and highlight three species that are particularly valuable for future investigations: the zebrafish, Danio rerio, the African Killifish, Nothobranchius furzeri, and the Mexican tetra, Astyanax mexicanus. This review is a part of a special issue on nutritional, hormonal, and metabolic drivers of development.
Retinoic acid (RA), derived from vitamin A, is a major teratogen, clinically recognized in 1983. Identification of its natural presence in the embryo and dissection of its molecular mechanism of action became possible in the animal model with the advent of molecular biology, starting with the cloning of its nuclear receptor. In normal development, the dose of RA is tightly controlled to regulate organ formation. Its production depends on enzymes, which have a dynamic expression profile during embryonic development. As a small molecule, it diffuses rapidly and acts as a morphogen. Here, we review advances in deciphering how endogenously produced RA provides positional information to cells. We compare three mesodermal tissues, the limb, the somites and the heart, and discuss how RA signalling regulates antero-posterior and left–right patterning. A common principle is the establishment of its spatio-temporal dynamics by positive and negative feedback mechanisms and by antagonistic signalling by FGF. However, the response is cell-specific, pointing to the existence of cofactors and effectors, which are as yet incompletely characterized.
This article is part of a discussion meeting issue ‘Contemporary morphogenesis’.
Retinoic acid (RA) is an active derivative of vitamin A and a key regulator of immune cell function. In dendritic cells (DCs), RA drives the expression of CD103 (integrin αE), a functionally relevant DC subset marker. In this study, we analyzed the cell type specificity and the molecular mechanisms involved in RA‐induced CD103 expression. We show that RA treatment caused a significant upregulation of CD103 in differentiated monocyte‐derived DCs and blood DCs, but not in differentiated monocyte‐derived macrophages or T cells. DC treatment with an RARα agonist lead to a similar increase in CD103 expression as RA treatment, while RARA gene silencing with siRNA blocked RA‐induced upregulation of CD103, pointing to a major role of RARα in the regulation of CD103 expression. To elucidate RA‐induced signaling downstream of RARα, we used Western blot analysis of RA‐treated DCs and showed a significant increase of p38 MAPK phosphorylation. In addition, DCs cultured with RA and a p38 MAPK inhibitor had a significantly reduced expression of CD103 compared with DCs cultured with RA only, indicating that p38 MAPK is involved in CD103 regulation. In summary, these findings suggest that the RA‐induced expression of CD103 is specific to DCs, is mediated primarily through RARα and involves p38 MAPK signaling.
In mouse, retinoic acid (RA) is required for the early phase of body axis extension controlled by a population of neuromesodermal progenitors (NMPs) in the trunk called expanding-NMPs, but not for the later phase of body axis extension controlled by a population of NMPs in the tail called depleting-NMPs. Recent observations suggest that zebrafish utilize depleting-NMPs but not expanding-NMPs for body axis extension. In zebrafish, a role for RA in body axis extension was not supported by previous studies on aldh1a2 (raldh2) mutants lacking RA synthesis. Here, by treating zebrafish embryos with an RA synthesis inhibitor, we also found that body axis extension and somitogenesis was not perturbed, although loss of pectoral fin and cardiac edema were observed consistent with previous studies. The conclusion that zebrafish diverges from mouse in not requiring RA for body axis extension is consistent with zebrafish lacking early expanding-NMPs to generate the trunk. We suggest that RA control of body axis extension was added to higher vertebrates during evolution of expanding-NMPs.
During development cells and tissues undergo changes in pattern and form that employ a wider range of physical mechanisms than at any other time in an organism's life. This book shows how physics can be used to analyze these biological phenomena. Written to be accessible to both biologists and physicists, major stages and components of the biological development process are introduced and then analyzed from the viewpoint of physics. The presentation of physical models requires no mathematics beyond basic calculus. Physical concepts introduced include diffusion, viscosity and elasticity, adhesion, dynamical systems, electrical potential, percolation, fractals, reaction-diffusion systems, and cellular automata. With full-color figures throughout, this comprehensive textbook teaches biophysics by application to developmental biology and is suitable for graduate and upper-undergraduate courses in physics and biology.
Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for vertebrate embryonic development because it is the molecular precursor of the essential signaling molecule RA. The level and distribution of RA signaling within a developing embryo must be tightly regulated; too much, or too little, or abnormal distribution, all disrupt embryonic development. Precise regulation of RA signaling during embryogenesis is achieved by proteins involved in vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. The reversible first step in conversion of the precursor vitamin A to the active retinoid RA is mediated by retinol dehydrogenase 10 (RDH10) and dehydrogenase/reductase (SDR family) member 3 (DHRS3), two related membrane-bound proteins that functionally activate each other to mediate the interconversion of retinol and retinal. Alcohol dehydrogenase (ADH) enzymes do not contribute to RA production under normal conditions during embryogenesis. Genes involved in vitamin A metabolism and RA catabolism are expressed in tissue-specific patterns and are subject to feedback regulation. Mutations in genes encoding these proteins disrupt morphogenesis of many systems in a developing embryo. Together these observations demonstrate the importance of vitamin A metabolism in regulating RA signaling during embryonic development in vertebrates.
Left–right (L–R) differences in mammographic parenchymal patterns are an early predictor of breast cancer risk; however, the basis for this asymmetry is unknown. Here, we use retinoid X receptor alpha heterozygous null (RXRα +/− ) mice to propose a developmental origin: perturbation of coordinated anterior–posterior (A–P) and L–R axial body patterning. We hypothesized that by analogy to somitogenesis—in which retinoic acid (RA) attenuation causes anterior somite pairs to develop L–R asynchronously—that RA pathway perturbation would likewise result in asymmetric mammary development. To test this, mammary glands of RXRα +/− mice were quantitatively assessed to compare left- versus right-side ductal epithelial networks. Unlike wild-type controls, half of the RXRα +/− thoracic mammary gland (TMG) pairs exhibited significant L–R asymmetry, with left-side reduction in network size. In RXRα +/− TMGs in which symmetry was maintained, networks had bilaterally increased size, with left networks showing greater variability in area and pattern. Reminiscent of posterior somites, whose bilateral symmetry is refractory to RA attenuation, inguinal mammary glands (IMGs) also had bilaterally increased network size, but no loss of symmetry. Together, these results demonstrate that mammary glands exhibit differential A–P sensitivity to RXRα heterozygosity, with ductal network symmetry markedly compromised in anterior but not posterior glands. As TMGs more closely model human breast development than IMGs, these findings raise the possibility that for some women, breast cancer risk may initiate with subtle axial patterning defects that result in L–R asymmetric growth and pattern of the mammary ductal epithelium.
This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.
Retinoicacid (RA) repression of Fgf8is required for many different aspects of organogenesis, however relatively little is known about how endogenous RA controls gene repression as opposed to gene activation. Here, we show that nuclear receptor corepressors NCOR1and NCOR2(SMRT) redundantly mediate the ability of RA to repress Fgf8.Ncor1;Ncor2double mutants generated by CRISPR/Cas9gene editing exhibited a small somite and distended heart phenotype similar to that of RA-deficient Raldh2-/-embryos, associated with increased Fgf8expression and FGF signaling in caudal progenitors and heart progenitors. Embryo chromatin immunoprecipitation studies revealed that NCOR1/2but not coactivators are recruited to the Fgf8RA response element (RARE) in an RA-dependent manner, whereas coactivators but not NCOR1/2are recruited RA-dependently to a RARE near Rarb that is activated by RA. CRISPR/Cas9-mediatedgenomic deletion of the Fgf8RARE in mouse embryos often resulted in a small somite defect with Fgf8derepression caudally, but no defect was observed in heart development or heart Fgf8expression. This suggests the existence of another DNA element whose function overlaps with the Fgf8RARE to mediate Fgf8repression by RA and NCOR1/2.Our studies support a model in which NCOR1/2mediates direct RA-dependent repression of Fgf8in caudal progenitors in order to control somitogenesis.
ONE OF THE MOST STRIKING FEATURES of the human spine is its periodic
organization. This so-called “segmental” arrangement of the vertebrae
along the anteroposterior body axis is established during embryonic
development. Structures called somites, which contain the precursors of
the vertebrae, form in a rhythmic fashion at the posterior end of the
embryo during the process of somitogenesis. Somites are sequentially
added to the growing axis, thus establishing the characteristic periodic
pattern of the future vertebral column. The primary segmentation of the
vertebrate embryo displayed by somitic organization also underlies much
of the segmental organization of the body, including muscles, nerves, and
blood vessels. In amniotes, somites are the major component of the
paraxial mesoderm that form bilaterally along the nerve cord as a result
of primitive streak and tail bud regression during body axis formation.
Somites bud off from the anterior presomitic mesoderm (PSM) as epithelial
spheres surrounding a core of mesenchymal cells called the somitocoele.
The dorsal portion of the somite remains epithelial and forms the
dermomyotome, which differentiates into muscle and dermis while its
ventral moiety undergoes an epithelio-mesenchymal transition, leading
to the formation of the sclerotome. The sclerotome gives rise to the skeletal
elements of the vertebral column: the vertebrae, ribs, intervertebral
disks, and tendons. Most of our understanding of amniote somitogenesis
at the morphogenetic and molecular levels results from studies involving
the chicken (Gallus gallus) and the mouse (Mus musculus). In this chapter,
we essentially focus on the patterning and development of the
spine in amniote species such as chickens, mice, and humans.
During vertebrate development, the paraxial mesoderm becomes segmented, forming somites that will give rise to dermis, axial skeleton and skeletal muscles. Although recently challenged, the "clock and wavefront" model for somitogenesis explains how interactions between several cell-cell communication pathways, including the FGF, RA, Wnt and Notch signals, control the formation of these bilateral symmetric blocks. In the cephalochordate amphioxus, which belongs to the chordate phylum together with tunicates and vertebrates, the dorsal paraxial mesendoderm also periodically forms somites, although this process is asymmetric and extends along the whole body. It has been previously shown that the formation of the most anterior somites in amphioxus is dependent upon FGF signalling. However , the signals controlling somitogenesis during posterior elongation in amphioxus are still unknown. Here we show that, contrary to vertebrates, RA and FGF signals act independently during posterior elongation and that they are not mandatory for posterior somites to form. Moreover, we show that RA is not able to buffer the left/right asymmetry machinery that is controlled through the asymmetric expression of Nodal pathway actors. Our results give new insights into the evolution of the somitogenesis process in chordates. They suggest that RA and FGF pathways have acquired specific functions in the control of somito-genesis in vertebrates. We propose that the "clock and wavefront" system was selected specifically in vertebrates in parallel to the development of more complex somite-derived structures but that it was not required for somitogenesis in the ancestor of chordates.
Bipotent axial stem cells residing in the caudal epiblast during late gastrulation generate neuroectodermal and presomitic mesodermal progeny that coordinate somitogenesis with neural tube formation, but the mechanism that controls these two fates is not fully understood. Retinoic acid (RA) restricts the anterior extent of caudal fibroblast growth factor 8 (Fgf8) expression in both mesoderm and neural plate to control somitogenesis and neurogenesis, however it remains unclear where RA acts to control the spatial expression of caudal Fgf8. Here, we found that mouse Raldh2-/- embryos, lacking RA synthesis and displaying a consistent small somite defect, exhibited abnormal expression of key markers of axial stem cell progeny, with decreased Sox2+ and Sox1+ neuroectodermal progeny and increased Tbx6+ presomitic mesodermal progeny. The Raldh2-/- small somite defect was rescued by treatment with an FGF receptor antagonist. Rdh10 mutants, with a less severe RA synthesis defect, were found to exhibit a small somite defect and anterior expansion of caudal Fgf8 expression only for somites 1-6, with normal somite size and Fgf8 expression thereafter. Rdh10 mutants were found to lack RA activity during the early phase when somites are small, but at the 6-somite stage RA activity was detected in neural plate although not in presomitic mesoderm. Expression of a dominant-negative RA receptor in mesoderm eliminated RA activity in presomitic mesoderm but did not affect somitogenesis. Thus, RA activity in the neural plate is sufficient to prevent anterior expansion of caudal Fgf8 expression associated with a small somite defect. Our studies provide evidence that RA restriction of Fgf8 expression in undifferentiated neural progenitors stimulates neurogenesis while also restricting the anterior extent of the mesodermal Fgf8 mRNA gradient that controls somite size, providing new insight into the mechanism that coordinates somitogenesis with neurogenesis.
The acquisition of a spatial structure during embryo development involves the differentiation of cells, often according to positional information. The complexity of the molecular networks regulating differentiation and of the mechanisms generating positional information makes it necessary to study them by means of mathematical modeling. Vertebrate embryos also acquire a segmented structure during somitogenesis; this requires spatial and temporal variations in gene expression, which mathematical modeling can also help understand.
A molecular mechanism for the somitogenesis clock is proposed, which accounts for inter-cellular synchronisation, and is based on positive feedback, even though it is compatible with all experimental data interpreted as showing that the clock is based on negative feedback. Experiments proposed to test this model involve real-time clock reporters, as well as inducible systems to induce spatially-controlled perturbations.
Theoretical and experimental results have led to conflicting ideas as to how useful positional information can be established. In particular, it has been pointed out that some models of extracellular diffusion of morphogen exhibit inadequate traveling waves of receptor saturation. Two alternative (but not mutually exclusive) models are proposed, which are based on recent experimental results highlighting the roles of extracellular glycoproteins and morphogen oligomerization.
The readout of positional information is translated to a discrete set of gene expression patterns. Intriguingly, it has been observed in numerous contexts that genes regulating differentiation are initially co-expressed in progenitors despite their antagonism. We characterise conditions under which three classes of generic "master regulatory networks" can behave as a "multi-switch", directing differentiation in an all-or-none fashion to a specific cell-type chosen among more than two possible outcomes. bHLH dimerisation networks can readily display coexistence of many antagonistic factors when competition is low. Decision-making can be forced by a transient increase in competition, which could correspond to some unexplained experimental observations related to Id proteins.
Growing evidence has proved that many aspects of our lifestyle and the environment contribute to the development of congenital disease. Congenital spinal deformities are due to anomalous development of the vertebrae including failure of formation and segmentation during embryogenesis. The causes of congenital scoliosis have not been fully identified. A variety of factors are implicated in the development of vertebral abnormalities. Previous studies have demonstrated that both genetics and environmental factors are implicated in the development of vertebral abnormalities. However, no specific cause for congenital scoliosis has been identified. In our review, we focus on the environmental factors for the development of congenital scoliosis. Various maternal exposures during pregnancy including hypoxia, alcohol use, vitamin deficiency, valproic acid, boric acid, and hyperthermia have been observed to be associated with the occurrence of congenital scoliosis. This review describes the major environmental contributors of congenital scoliosis with an emphasis on treatment aspects associated with environmental disposition in congenital scoliosis.
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