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The process of embryonic development involves remarkable cellular plasticity, which governs the coordination between cells necessary to build an organism. One role of this plasticity is to ensure that when aberrant cells are eliminated, growth adjustment occurs so that the size of the tissue is maintained. An important regulator of cellular plasticity that ensures cellular cooperation is a fitness-sensing mechanism termed cell competition. During cell competition, cells with defects that lower fitness but do not affect viability, such as those that cause impaired signal transduction, slower cellular growth, mitochondrial dysregulation or impaired protein homeostasis, are killed when surrounded by fitter cells. This is accompanied by the compensatory proliferation of the surviving cells. The underlying factors and mechanisms that demarcate certain cells as less fit than their neighbouring cells and losers of cell competition are still relatively unknown. Recent evidence has pointed to mitochondrial defects and proteotoxic stress as important hallmarks of these loser cells. Here, we review recent advances in this area, focussing on the role of mitochondrial activity and protein homeostasis as major mechanisms determining competitive cell fitness during development and the importance of cell proteostasis in determining cell fitness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The extraembryonic endoderm of mammals is essential for nutritive support of the fetus and patterning of the early embryo. Visceral and parietal endoderm are major subtypes of this lineage with the former exhibiting most, if not all, of the embryonic patterning properties. Extraembryonic endoderm (XEN) cell lines derived from the primitive endoderm of mouse blastocysts represent a cell culture model of this lineage, but are biased towards parietal endoderm in culture and in chimeras. In an effort to promote XEN cells to adopt visceral endoderm character we have mimicked different aspects of the in vivo environment. We found that BMP signaling promoted a mesenchymal-to-epithelial transition of XEN cells with up-regulation of E-cadherin and down-regulation of vimentin. Gene expression analysis showed the differentiated XEN cells most resembled extraembryonic visceral endoderm (exVE), a subtype of VE covering the extraembryonic ectoderm in the early embryo, and during gastrulation it combines with extraembryonic mesoderm to form the definitive yolk sac. We found that laminin, a major component of the extracellular matrix in the early embryo, synergised with BMP to promote highly efficient conversion of XEN cells to exVE. Inhibition of BMP signaling with the chemical inhibitor, Dorsomorphin, prevented this conversion suggesting that Smad1/5/8 activity is critical for exVE induction of XEN cells. Finally, we show that applying our new culture conditions to freshly isolated parietal endoderm (PE) from Reichert's membrane promoted VE differentiation showing that the PE is developmentally plastic and can be reprogrammed to a VE state in response to BMP. Generation of visceral endoderm from XEN cells uncovers the true potential of these blastocyst-derived cells and is a significant step towards modelling early developmental events ex vivo., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In the mouse, embryological and genetic studies have indicated that two spatially distinct signalling centres, the anterior visceral endoderm and the node and its derivatives, are required for the correct patterning of the anterior neural ectoderm. The divergent homeobox gene Hex is expressed in the anterior visceral endoderm, in the node (transiently), and in the anterior definitive endoderm. Other sites of Hex expression include the liver and thyroid primordia and the endothelial cell precursors. We have used transgenic analysis to map the cis-acting regulatory elements controlling Hex expression during early mouse development. A 4.2-kb upstream region is important for Hex expression in the endothelial cell precursors, liver, and thyroid, and a 633-bp intronic fragment is both necessary and sufficient for Hex expression in the anterior visceral endoderm and the anterior definitive endoderm. These same regions drive expression in homologous structures in Xenopus laevis, indicating conservation of these regulatory regions in vertebrates. Analysis of the anterior visceral endoderm/anterior definitive endoderm enhancer identifies a repressor region that is required to downregulate Hex expression in the node once the anterior definitive endoderm has formed. This analysis also reveals that the initiation of Hex expression in the anterior visceral endoderm and axial mesendoderm requires common elements, but maintenance of expression is regulated independently in these tissues., (Copyright 2001 Academic Press.)

The homeobox gene Hesx1 is expressed in the anterior visceral endoderm (AVE), anterior axial mesendoderm (AME), and anterior neural ectoderm (ANE) during early mouse embryogenesis. Previous studies have shown that Hesx1 is essential for normal murine forebrain development. Hesx1 homozygous mutants showed variable forebrain truncations ranging from mild to severe lack of forebrain tissue. Here, we have investigated the requirement of Hesx1 in the AVE, AME, and ANE using chimeric and in situ hybridization analyses to understand better the nature of the forebrain defects. Chimeric embryos composed predominantly of Hesx1(+/+) cells developing within Hesx1(-/-) visceral endoderm showed no evident forebrain abnormalities. In contrast, injection of Hesx1(-/-) ES cells into wild-type blastocysts gave rise to chimeras with forebrain defects similar to those observed in the Hesx1(-/-) mutants. RNA in situ hybridization analysis showed that the AVE and AME markers Cerrl, Lim1, and Shh were normally expressed in 6.5- and 7.5-dpc Hesx1(-/-) mutants. Expression of the ANE markers Six3 and Rax/Rx was also unperturbed in the Hesx1(-/-) mutants from late gastrula to late headfold stages. However, transcripts for both genes were markedly reduced by the early somite stage, about 24 h after Hesx1 is first expressed in the ANE. Therefore, Hesx1 seems to be required autonomously in the ANE for normal forebrain formation., (Copyright 2000 Academic Press.)

Msg1 and Mrg1 are founding members of a gene family which exhibit distinct patterns of gene expression during mouse embryogenesis. Sequence analysis reveals that these genes are unlike any other gene identified to date, but they share two near-identical sequence domains. The Msg1 and Mrg1 expression profiles during early development are distinct from each other. Msg1 is predominantly expressed in nascent mesoderm, the heart tube, limb bud and sclerotome. Intriguingly, Msg1 expression is restricted, within these developing mesodermal sites, to posterior domains. Mrg1 is expressed prior to gastrulation in the anterior visceral endoderm. Expression is maintained in the endoderm once gastrulation has begun and commences in the rostralmost embryonic mesoderm which underlies the anterior visceral endoderm. Mrg1 expression persists in this rostral mesoderm as it is translocated caudalwards during the invagination of the foregut and the formation of the heart. Later Mrg1 expression predominates in the septum transversum caudal to the heart. This expression pattern suggests that the septum transversum originates from the rostralmost embryonic mesoderm which first expressed Mrg1 at the late primitive streak stage., (Copyright 1998 Elsevier Science Ireland Ltd.)