Abstract
SummaryAt implantation, the embryo establishes contacts with the maternal endometrium. This stage is associated with a high incidence of preclinical pregnancy losses. While the maternal factors underlying uterine receptivity have been investigated, the signals required by the embryo for successful peri-implantation development remain elusive. To explore these, we studied integrin β1 signaling, as embryos deficient for this receptor degenerate at implantation. We demonstrate that the coordinated action of pro-survival signals and localized actomyosin suppression via integrin β1 permits the development of the embryo beyond implantation. Failure of either process leads to developmental arrest and apoptosis. Pharmacological stimulation through fibroblast growth factor 2 (FGF2) and insulin-like growth factor 1 (IGF1), coupled with ROCK-mediated actomyosin inhibition, rescues the deficiency of integrin β1, promoting progression to post-implantation stages. Mutual exclusion between integrin β1 and actomyosin seems to be conserved in the human embryo, suggesting the possibility that these mechanisms could also underlie the transition of the human epiblast from pre- to post-implantation.
Highlights
Implantation is a critical stage of mammalian embryogenesis (Aplin and Ruane, 2017; Cha et al, 2012; Geisert and Fuller, 2015)
To explore the molecular process leading to lethality of the embryo in the absence of integrin b1, we derived a conditional mouse embryonic stem cell line from homozygous embryos carrying the Itgb1 floxed allele (Potocnik et al, 2000) and cultured them for 24, 48, and 72 h under differentiating conditions in 3D to recapitulate peri-implantation morphogenesis of the embryonic lineage in vitro (Shahbazi and Zernicka-Goetz, 2018)
These cells did not display any sign of apoptosis after 24 h (Figure 1A, top), and only 13% of the structures contained cells positive for cleaved caspase-3 at 48 h (Figure 1B, top)
Summary
Implantation is a critical stage of mammalian embryogenesis (Aplin and Ruane, 2017; Cha et al, 2012; Geisert and Fuller, 2015). While the molecular factors underlying uterine receptivity have been extensively investigated (Cakmak and Taylor, 2011; Cha et al, 2012; Koot et al, 2012), the signaling necessary for the embryo proper to develop through implantation remains largely unexplored. While embryos deficient for integrin b1 successfully implant into the endometrium, they fail to progress beyond this stage (Stephens et al, 1995). A similar phenotype of embryonic peri-implantation lethality could be observed when the integrin ligands laminin b1 (Miner et al, 2004) and laminin g1 (Smyth et al, 1999) or key downstream factors such as integrin-linked kinase (ILK) (Sakai et al, 2003) and Pinch (Li et al, 2005) were lost, pointing toward a critical requirement for integrin signaling during progression of the mammalian embryo beyond implantation (Sutherland et al, 1993). Loss of integrin-mediated signaling has been correlated with the inability of cells to organize into polarized structures, both in the context of embryonic stem cells (ESCs) as well as in models of in vivo and in vitro epithelial
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