Consolidation of cell-ECM adhesion through direct talin-mediated actin linkage is essential for mouse embryonic...

During animal development, cell-ECM adhesion mediated by integrins is required for the assembly and maintenance of tissues and organs. It can either be transient or stable and requires linking integrins to the cytoskeleton. Talin can link integrins to actin either directly through its actin-binding sites (ABSs) or indirectly by recruiting downstream actin-binding molecules. In Drosophila, talin's ABS3 domain is essential for biological functions, but its role remains unknown in mammalian systems. Here, we investigate the role of direct talin-mediated actin linkage in mammals by generating a mouse model containing point mutations in talin's ABS3 domain. We find that mutant mice exhibit early developmental defects and die midway through embryogenesis. Primary mouse embryonic fibroblasts generated from mutants form prominent focal adhesions but show defective consolidation and maturation. Adhesion dynamics, cell spreading, actin dynamics and organization, and traction force generation are also impacted in mutants, which affect processes such as cell migration that impinge on multiple events during early mouse embryogenesis. Overall, our work provides key mechanistic insights into how direct coupling of ECM to actin through talin has specific and critical roles in controlling adhesion dynamics required for early mammalian development.