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Abstract

A cell’s perception of its position within the tissue critically underlies spatially patterned differentiation and ultimately drives development. However, our understanding of the molecular mechanisms by which individual cells acquire and transmit positional information remains incomplete. By using the mouse model, the present thesis demonstrates how developmentally controlled adhesive interactions enable position-sensing by cells to pattern the preimplantation embryo. The mouse embryo is initially a cluster of transcriptionally and geometrically equivalent cells. During the 16-32-cell stage, however, spatial differences emerge, closely followed by the first lineage segregation. Outer cells become trophectoderm (TE)-specified while inner cells give rise to the inner cell mass (ICM), which go on to form the extraembryonic tissues and the embryo proper, respectively. While outer cells are marked by a polarised apical domain on the cell-free surface, inner cells are enveloped by adhesive cell-cell interfaces. By characterising and manipulating the adhesive environment of early embryonic cells, the work presented here illustrates that stage-specific activity of integrins and the extracellular matrix (ECM) at these cell-cell interfaces distinguish the embryonic interior. Immunosurgical isolation of inner cells prior to their lineage commitment removes existing intercellular adhesions and subsequently drives TE specification. In marked contrast, however, provision of exogenous ECM components induces ICM specification instead, and this response is dependent on integrin 1 activity. Our findings suggest that interactions between integrins and their ECM ligands convey inner positional information for inside-outside patterning of the preimplantation embryo. Furthermore, even in the presence of molecules that mediate direct intercellular adhesion, the ECM is required at the cell-cell interface to prompt position-sensing. While cell-cell and cell-ECM adhesions are commonly considered to be spatially distinct, the present work indicates that ECM components are also present at the cell-cell interface to critically influence patterning. Given the ubiquity of the ECM among metazoans, we predict that future studies would increasingly uncover morphogenetic requirements for intercellular ECM.