Epiblast

Summary

In amniote embryonic development, the epiblast (also known as the primitive ectoderm) is one of two distinct cell layers arising from the inner cell mass in the mammalian blastocyst, or from the blastula in reptiles and birds, the other layer is the hypoblast. It derives the embryo proper through its differentiation into the three primary germ layers, ectoderm, mesoderm and endoderm, during gastrulation. The amnionic ectoderm and extraembryonic mesoderm also originate from the epiblast. The other layer of the inner cell mass, the hypoblast, gives rise to the yolk sac, which in turn gives rise to the chorion. The epiblast was first discovered by Christian Heinrich Pander (1794-1865), a Baltic German biologist and embryologist. With the help of anatomist Ignaz Döllinger (1770–1841) and draftsman Eduard Joseph d'Alton (1772-1840), Pander observed thousands of chicken eggs under a microscope, and ultimately discovered and described the chicken blastoderm and its structures, including the epiblast. He published these findings in Beiträge zur Entwickelungsgeschichte des Hühnchens im Eye. Other early embryologists that studied the epiblast and blastoderm include Karl Ernst von Baer (1792-1876) and Wilhelm His (1831-1904). In mammalian embryogenesis, differentiation and segregation of cells composing the inner cell mass of the blastocyst yields two distinct layers—the epiblast ("primitive ectoderm") and the hypoblast ("primitive endoderm"). While the cuboidal hypoblast cells delaminate ventrally, away from the embryonic pole, to line the blastocoele, the remaining cells of the inner cell mass, situated between the hypoblast and the polar trophoblast, become the epiblast and comprise columnar cells. In the mouse, primordial germ cells are specified from epiblast cells. This specification is accompanied by extensive epigenetic reprogramming that involves global DNA demethylation, chromatin reorganization and imprint erasure leading to totipotency. The DNA base excision repair pathway has a central role in the process of genome-wide demethylation.

Official source

https://en.wikipedia.org/wiki/Epiblast

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In vitro modeling of early mouse development

Mehmet Ugur Girgin

Previous attempts to recapitulate embryogenesis in a developmentally relevant context started with aggregates composed of a few thousand ESCs, termed embryoid bodies (EB), that upon induction of differentiation reveal a surprising level of autonomous cell fate patterning, in some cases giving rise to spatially arranged ectoderm, mesoderm and endoderm layers. However, cell fate patterning and morphogenesis in EBs is poorly reproducible and cannot be controlled. These limitations necessitate further research on the self-organization potential of ESCs, and in particular the development of more robust in vitro models mimicking post-implantation mouse embryos. This PhD thesis explored three novel approaches towards this goal. Firstly, together with collaborators, I focused on a previously established in vitro model of gastrulation termed gastruloids. Gastruloids emerge from small ESC aggregates that, upon activation of Wnt signaling, break symmetry and undergo axial morphogenesis to create structures that are similar to the developing tail of the mouse embryo. A systematic improvement of the existing culture conditions allowed gastruloids to be cultured for an extended period of time, resulting in an embryo-like patterning along the three major body axes. Furthermore, gene expression analyses, combined with immunohistochemistry and in situ hybridization assays, demonstrated that gastruloids exhibit spatio-temporal activation of Hox genes in a way that is remarkably similar to post-implantation mouse embryos. Secondly, I report a novel gastruloid culture approach, which for the first time promotes the formation of anterior neural tissues. Mouse ESCs were aggregated and treated in high-throughput in a bioengineered microwell array system to generate homogeneous âartificial epiblastsâ that transcriptionally and morphologically resemble post-implantation epiblasts. These epiblast-like (EPI) aggregates break symmetry and undergo axial elongation to establish antero-posterior patterning. I provide evidence for attenuated Wnt signaling and the presence of an epithelium in the starting EPI aggregates as the major determinants for the formation of anterior neural tissues, that are completely absent in conventional gastruloids. Lastly, I systematically explored the role of extraembryonic tissues in the patterning of artificial epiblasts. By combining EPI aggregates with trophoblast stem cell aggregates, hybrid self-organizing structures termed EpiTS embryoids were generated that mimic epiblast and extraembryonic ectoderm, respectively. EpiTS embryoids were found to execute an elaborate self-organization program that is initiated through highly localized gastrulation-like processes at the embryonic-extraembryonic interface. Upon axial elongation, EpiTS embryoids give rise to primitive brain-like and preplacodal ectoderm-like regions. These observations highlight the role of extraembryonic tissues for proper induction of gastrulation and in particular the formation of anterior neural tissues. Altogether, this thesis introduces three innovative and highly versatile stem cell culture technologies to study post-implantation mouse embryonic development. The approaches are amenable to large-scale studies aimed at identifying novel regulators of gastrulation and anterior neural development that is currently out of reach with existing experimental tools. This work should contribute to the advancement of the nascent field of synthetic embryology.

EPFL2020

Epiblast-specific loss of HCF-1 leads to failure in anterior-posterior axis specification

Daniel Constam, Winship Herr, Sylvain Frédéric Bessonnard

Mammalian Host-Cell Factor 1 (HCF-1), a transcriptional co-regulator, plays important roles during the cell-division cycle in cell culture, embryogenesis as well as adult tissue. In mice, HCF-1 is encoded by the X-chromosome-linked Hcfc1 gene. Induced Hcfc1(cKO/+) heterozygosity with a conditional knockout (cKO) allele in the epiblast of female embryos leads to a mixture of HCF-1-positive and -deficient cells owing to random X-chromosome inactivation. These embryos survive owing to the replacement of all HCF-1-deficient cells by HCF-1-positive cells during E5.5 to E8.5 of development. In contrast, complete epiblast-specific loss of HCF-1 in male embryos, Hcfc1(epiko/Y), leads to embryonic lethality. Here, we characterize this lethality. We show that male epiblast-specific loss of Hcfc1 leads to a developmental arrest at E6.5 with a rapid progressive cell-cycle exit and an associated failure of anterior visceral endoderm migration and primitive streak formation. Subsequently, gastrulation does not take place. We note that the pattern of Hcfc1(epiKO/y) lethality displays many similarities to loss of beta-catenin function. These results reveal essential new roles for HCF-1 in early embryonic cell proliferation and development. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

Academic Press Inc Elsevier Science2016

Nodal and its co-receptors of the EGF-CFC family are essential during chordate development, both to maintain pluripotent progenitor cells and to subsequently coordinate their allocation to the different germ layers. How these distinct Nodal activities are kept in balance is unknown. Previous work in our laboratory established that the Nodal proprotein must be cleaved by proprotein convertases (PC) to induce itself on time in the mouse epiblast. However, expression of a knock-in allele encoding a PC-resistant mutant Nodal precursor (Nr) is sufficient to induce a subset of Nodal target genes during gastrulation, including Fgf4 in the epiblast, and Bmp4 in extraembryonic ectoderm (ExE). Here, I extend these findings by showing that these NodalNr/Nr embryos also partially maintain a panel of trophoblast stem cell (TSC) markers. To better define how Nodal maintains pluripotency and how it might signal to TSCs in the ExE, and as a means to genetically uncouple Nodal production from processing, I treated cultured TSCs and NodallacZ/lacZ embryonic stem cells (ESCs) with recombinant Nodal or with cleavage-resistant mutant Nodal precursor. I show that recombinant mature Nodal stimulates Smad2 phosphorylation in both ESCs and TSCs, even though the latter do not express Nodal coreceptors of the EGF-CFC family. In contrast, recombinant Nr failed to activate the canonical Smad pathway in either cell type, and hence preferentially stimulated Jnk and p38 MAPK signaling. Yet, none of these activities were sufficient to promote self-renewal of mouse ESCs or TSCs under any of the culture conditions examined. Using lentiviral overexpression of constitutively active receptors with mutations in the Smad2,3 binding site, I observed that TSC stemness apparently can be maintained independently of Smad2,3 activation. These results suggest that mature Nodal or its unprocessed precursor likely promote the self-renewal of TSCs in vivo through a non-canonical, Smad-independent signaling pathway, but that available recombinant proteins for unknown reasons cannot fully mimic this activity in vitro, at least under the conditions examined.

EPFL2011

In vitro modeling of early mouse development

Mehmet Ugur Girgin

EPFL2020

EPFL2011