Inside-out integrin activation is essential for early mammalian development.

The attachment of cells to the extracellular matrix (ECM) is essential for morphogenesis. The activity of Integrins, the main mediators of cell-ECM adhesion in animals, is required for morphogenesis and must be precisely regulated to ensure proper development. However, the mechanisms that ensure precise integrin activity during animal development are poorly understood. The best characterized mechanism for integrin regulation is conformational change driven by either extracellular signals ("outside-in activation") or by intracellular signals ("inside-out activation"). The cytoplasmic protein talin is a key regulator of inside-out activation. We used mutations in talin to demonstrate, for the first time, that modulation of integrin activation is essential for early mammalian development. We find that integrin activation mutants die by E8.5-E9.5 and show developmental delay and abnormal growth. Intriguingly, disrupting integrin regulation does not impinge on embryonic patterning and ECM distribution. Analysis of embryonic stem cells isolated from integrin activation mutants revealed a reduction in the strength of cell-ECM attachment but only mild defects in focal adhesion number and maturation. Notably, activation mutants at E7.5 showed increased cell death and reduced cell-proliferation Overall, we find that inside-out integrin activation strengthens cell-ECM attachment in early mouse development that is essential for cell survival and proliferation.