Amnion signals are essential for mesoderm formation in primates.
Ontology highlight
ABSTRACT:
SUBMITTER: Yang R
PROVIDER: S-EPMC8390679 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Embryonic development is largely conserved among mammals. However, certain genes show divergent functions. By generating a transcriptional atlas containing >30,000 cells from post-implantation non-human primate embryos, we uncover that ISL1, a gene with a well-established role in cardiogenesis, controls a gene regulatory network in primate amnion. CRISPR/Cas9-targeting of ISL1 results in non-human primate embryos which do not yield viable offspring, demonstrating that ISL1 is critically required in primate embryogenesis. On a cellular level, mutant ISL1 embryos display a failure in mesoderm formation due to reduced BMP4 signaling from the amnion. Via loss of function and rescue studies in human embryonic stem cells we confirm a similar role of ISL1 in human in vitro derived amnion. This study highlights the importance of the amnion as a signaling center during primate mesoderm formation and demonstrates the potential of in vitro primate model systems to dissect the genetics of early human embryonic development.
2021-06-30 | GSE148683 | GEO
Project description:Amnion signals are essential for mesoderm formation in primates
| PRJNA625334 | ENA
Project description:Mammalian Argonaute proteins (EIF2C1-4) play an essential role in RNA-induced silencing. Here, we show that the loss of eIF2C2 (Argonaute2 or Ago2) results in gastrulation arrest, ectopic expression of Brachyury (T), and mesoderm expansion. We identify a genetic interaction between Ago2 and T, as Ago2 haploinsufficiency partially rescues the classic T/+ short-tail phenotype. Finally, we demonstrate that the ectopic T expression and concomitant mesoderm expansion result from disrupted fibroblast growth factor signaling, likely due to aberrant expression of Eomesodermin. Together, these data indicate that a factor best known as a key component of the RNA-induced silencing complex is required for proper fibroblast growth factor signaling during gastrulation, suggesting a possible micro-RNA function in the formation of a mammalian germ layer.
| S-EPMC2323323 | biostudies-literature
Project description:The T box transcription factor Brachyury is essential for the formation of the posterior body in all vertebrates, although its critical transcriptional targets have remained elusive. Loss-of-function studies of mouse Brachyury and the zebrafish Brachyury ortholog Ntl indicated that Brachyury plays a more significant role in higher vertebrates than lower vertebrates. We have identified a second zebrafish Brachyury ortholog (Bra), and show that a combined loss of Ntl and Bra recapitulates the mouse phenotype, demonstrating an ancient role for Brachyury in patterning all but the most anterior somites. Using cell transplantation, we show that the only essential role for Brachyury during somite formation is non-cell autonomous, and demonstrate that Ntl and Bra are required for and can induce expression of the canonical Wnts wnt8 and wnt3a. We propose that a positive autoregulatory loop between Ntl/Bra and canonical Wnt signaling maintains the mesodermal progenitors to facilitate posterior somite development in chordates.
| S-EPMC2601683 | biostudies-literature
Project description:Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood. Differential requirements for p53 inhibitors Mdm2 and Mdm4 during development suggest that these control mechanisms are context-dependent. Artery formation requires investment of nascent endothelial tubes by smooth muscle cells (SMCs). Here, we find that embryos lacking SMC ?-catenin suffer impaired arterial maturation and die by E12.5, with increased vascular wall p53 activity. ?-Catenin-deficient SMCs show no change in p53 levels, but greater p53 acetylation and activity, plus impaired growth and survival. In vivo, SMC p53 inactivation suppresses phenotypes caused by loss of ?-catenin. Mechanistically, ?-catenin C-terminal interactions inhibit Creb-binding protein-dependent p53 acetylation and p53 transcriptional activity, and are required for artery formation. Thus in SMCs, the ?-catenin C-terminus indirectly represses p53, and this function is essential for embryogenesis. These findings have implications for angiogenesis, tissue engineering and vascular disease.
| S-EPMC4979065 | biostudies-literature
Project description:Amnion-derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of a common transcription factor driving the expression of both cyclooxygenase-2 (COX-2) and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), the key enzymes in their production, may hold the key to the treatment of pre-term labor. Here, we have found that the CCAAT enhancer binding protein δ (C/EBPδ) is such a transcription factor which underlies the feed-forward induction of COX-2 and 11β-HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPδ in the amnion increases along with COX-2 and 11β-HSD1 at term and further increases at parturition. Knockout of C/EBPδ in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPδ pathway may be speculated to serve as a potential pharmaceutical target in the amnion for treatment of pre-term labor.
| S-EPMC8191398 | biostudies-literature
Project description:Previous studies have shown that P19 cells expressing a dominant negative ?-catenin mutant (?-cat/EnR) cannot undergo myogenic differentiation in the presence or absence of muscle-inducing levels of retinoic acid (RA). While RA could upregulate premyogenic mesoderm expression, including Pax3/7 and Meox1, only Pax3/7 and Gli2 could be upregulated by RA in the presence of ?-cat/EnR. However, the use of a dominant negative construct that cannot be compensated by other factors is limiting due to the possibility of negative chromatin remodelling overriding compensatory mechanisms. In this study, we set out to determine if ?-catenin function is essential for myogenesis with and without RA, by creating P19 cells with reduced ?-catenin transcriptional activity using an shRNA approach, termed P19[sh?-cat] cells. The loss of ?-catenin resulted in a reduction of skeletal myogenesis in the absence of RA as early as premyogenic mesoderm, with the loss of Pax3/7, Eya2, Six1, Meox1, Gli2, Foxc1/2, and Sox7 transcript levels. Chromatin immunoprecipitation identified an association of ?-catenin with the promoter region of the Sox7 gene. Differentiation of P19[sh?-cat] cells in the presence of RA resulted in the upregulation or lack of repression of all of the precursor genes, on day 5 and/or 9, with the exception of Foxc2. However, expression of Sox7, Gli2, the myogenic regulatory factors and terminal differentiation markers remained inhibited on day 9 and overall skeletal myogenesis was reduced. Thus, ?-catenin is essential for in vitro formation of premyogenic mesoderm, leading to skeletal myogenesis. RA can at least partially compensate for the loss of ?-catenin in the expression of many myogenic precursor genes, but not for myoblast gene expression or overall myogenesis.
| S-EPMC3583846 | biostudies-literature
Project description:BackgroundDespite the detailed knowledge obtained over the last decade on the molecular regulation of gastrulation in amniotes, the process of amnion development has been poorly described and illustrated in mice, and conflicting descriptions exist. Understanding the morphogenesis and development not only of the early mouse embryo, but also of its extraembryonic tissues, is crucial for correctly interpreting fate-mapping data and mouse mutants with gastrulation defects. Moreover, the recent isolation from amnion of cells with stem cell features further argues for a better understanding of the process of amnion formation. Here, we revisit the highly dynamic process of amnion formation in the mouse. Amnion development starts early during gastrulation and is intimately related to the formation of the exocoelom and the expansion of the amniotic fold. The authoritative description involves the fusion of two amniotic folds, a big posterior and a smaller anterior fold. We challenged this 'two amniotic folds' model by performing detailed histomorphological analyses of dissected, staged embryos and 3D reconstructions using historical sections.ResultsA posterior fold of extraembryonic ectoderm and associated epiblast is formed early during gastrulation by accumulation of extraembryonic mesoderm posterior to the primitive streak. Previously called the "posterior amniotic fold", we rename it the "amniochorionic fold" (ACF) because it forms both amnion and chorion. Exocoelom formation within the ACF seems not to involve apoptosis within the mesoderm. The ACF and exocoelom expand without disrupting the anterior junction of epiblast, extraembryonic ectoderm and visceral endoderm. No separate anterior fold is formed; its absence was confirmed in 3D reconstructions. Amnion and chorion closure is eccentric, close to the anterior margin of the egg cylinder: we name it the "anterior separation point".ConclusionsHere, we reconcile previous descriptions of amnion formation and provide new nomenclature, as well as an animation, that clarify and emphasize the arrangement of the tissues that contribute to amnion development and the dynamics of the process. According to our data, the amnion and the chorion are formed by a single amniochorionic fold initiated posteriorly. Finally, we give an overview on mutant mouse models with impaired amnion development.
| S-EPMC3163621 | biostudies-literature
Project description:R-spondins are a family of secreted proteins that play important roles in embryonic development and cancer. R-spondins have been shown to modulate the Wnt pathway; however, their involvement in other developmental signaling processes have remained largely unstudied. Here, we describe a novel function of Rspo2 in FGF pathway regulation in vivo Overexpressed Rspo2 inhibited elongation of Xenopus ectoderm explants and Erk1 activation in response to FGF. By contrast, the constitutively active form of Mek1 stimulated Erk1 even in the presence of Rspo2, suggesting that Rspo2 functions upstream of Mek1. The observed inhibition of FGF signaling was accompanied by the downregulation of the FGF target genes tbxt/brachyury and cdx4, which mediate anterioposterior axis specification. Importantly, these target genes were upregulated in Rspo2-depleted explants. The FGF inhibitory activity was mapped to the thrombospondin type 1 region, contrasting the known function of the Furin-like domains in Wnt signaling. Further domain analysis revealed an unexpected intramolecular interaction that might control Rspo2 signaling output. We conclude that, in addition to its role in Wnt signaling, Rspo2 acts as an FGF antagonist during mesoderm formation and patterning.
| S-EPMC7272350 | biostudies-literature
Project description:Establishment of the embryonic mesoderm is dependent on integration of multiple signaling and transcriptional inputs. We report that the transcriptional regulator Foxd3 is essential for dorsal mesoderm formation in zebrafish, and that this function is dependent on the Nodal pathway. Foxd3 gain-of-function results in expanded dorsal mesodermal gene expression, including the Nodal-related gene cyclops, and body axis dorsalization. Foxd3 knockdown embryos displayed reduced expression of cyclops and mesodermal genes, axial defects similar to Nodal pathway loss-of-function, and Nodal pathway activation rescued these phenotypes. In MZoep mutants inactive for Nodal signaling, Foxd3 did not rescue mesoderm formation or axial development, indicating that the mesodermal function of Foxd3 is dependent on an active downstream Nodal pathway. A previously identified foxd3 mutant, sym1, was described as a predicted null mutation with neural crest defects, but no mesodermal or axial phenotypes. We find that Sym1 protein retains activity and can induce strong mesodermal expansion and axial dorsalization. A subset of sym1 homozygotes displays axial defects and reduced cyclops and mesodermal gene expression, and penetrance of the mesodermal phenotypes is enhanced by Foxd3 knockdown. Therefore, sym1 is a hypomorphic allele, and reduced Foxd3 function results in a reduction of cyclops expression, and subsequent mesodermal and axial defects. These results demonstrate that Foxd3 is an essential upstream regulator of the Nodal pathway in zebrafish dorsal mesoderm development and establish a broadly conserved role for Foxd3 in vertebrate mesodermal development.
| S-EPMC2866760 | biostudies-literature