Integrin β1 coordinates survival and morphogenesis of the embryonic lineage upon implantation and pluripotency transition

Abstract

Summary At 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.

E-cadherin mediated Apical Membrane Initiation Site localisation

“…It is possible that there is a differentially higher pattern of tension at this most central point of contact between two adhering cells. In line with this hypothesis, previous publications have demonstrated an upregulation of phosphorylated MYOSIN-II (pMLC) at the AMIS (Molè et al, 2021).…”

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

“…Our observations, compared with previous findings that activity of formins but not Arp2/3 complex is necessary for EMT and the assembly of unbranched contractile actin filaments (Li et al, 2010;Jurmeister et al, 2012;Rana et al, 2018), indicate that these different classes of actin nucleators and the architectures they generate have selective roles in distinct types of epithelial plasticity. With known functions in migration (Suraneni et al, 2012;Arnold 2008) and adherens junction tension (Verma et al, 2012;Fierro-Gonzales et al, 2012), there are abundant potential mechanisms whereby Arp2/3 complex activity might regulate mESC pluripotency transition (Rotty et al, 2013;Pieters and van Roy, 2014;Wagh et al, 2021;Molé et al, 2021). Our study provides a step toward closing the gap between phenotype and genotype, opening new directions and advancing new approaches to understand how morphological changes and actin filament dynamics promote pluripotency transition, with potential value for additional approaches in directing differentiations for regenerative medicine.…”

“…A mechanism for changes in mESC morphology by actin remodeling and how they are regulated in the context of differentiation and lineage specification remains incompletely understood. Recent advances proposed roles for dynamic cell membrane tension and polarity as requisite regulators of both in vitro mESC differentiation (Xia et al, 2019;Bergert, Lembo et al, 2021) and in vivo embryonic development (Molé et al, 2021); however, to our knowledge a direct link between actin-dependent changes in morphology and the transcriptional programming of lineage specification has not been reported. To quantify changes in mESC colony morphology in real time we used quantitative DIC imaging of naive E14 mESCs maintained in the presence of LIF2i (Leukemia Inhibitory Factor and pharmacological inhibitors PD0325901 for MEK and CHIR99021 for glycogen synthase kinase-3β) and spontaneously differentiated for 72h after removal of LIF2i (Ying et al, 2008).…”

“…Changes in cell morphology are often not driven by actin filament remodeling alone but also in combination with actomyosin contractility (Murrell et al, 2015). In human induced pluripotent cells (iPSCs), a contractile actin fence promotes pluripotency and in mouse embryos suppressing actomyosin contractility regulates epiblast morphogenesis during pre-to postimplantation (Närvä et al, 2017;Molé et al, 2021). Consistent with our finding that CK666 attenuates changes in mESC colony morphology, immunolabeling indicates that phosphorylated MLC (pMLC), an indicator of actomyosin contractility, decorates the cortical actin ring around cells and the peripheral ring around free margins of colonies in control naïve mESCs but is diffuse in the cytoplasm after 72h -LIF2i (Fig.…”

Changes in the Mitochondria-Related Nuclear Gene Expression Profile during Human Oocyte Maturation by the IVM Technique

“…For instance, in contrast to M-IVO, M-IVT oocytes were very different with respect to cell–substrate adherens junction, cell–substrate junction, focal adhesion, and protein targeting. These biological dysfunctions are related to the survival and morphogenesis of an embryonic lineage upon implantation and pluripotency transition [ 27 , 28 ], which may be the reason why the implantation rate of embryos derived from IVM oocyte is lower than that of embryos from in vivo matured oocytes in clinical applications. Regarding mitochondria-related gene expression, there were 160 DEGs that were mitochondria related, including 111 that were up-regulated and 49 that were down-regulated.…”