Mouse scalp development requires Rac1 and SRF for the maintenance of mechanoresponsive mesenchyme.

Rac1 is a small GTPase that regulates cell proliferation, migration and differentiation processes crucial for development. Mutations in specific guanine nucleotide exchange factors and GTPases that regulate Rac1 are associated with Adams-Oliver syndrome (AOS), a syndrome characterized by congenital scalp defects and limb truncations. Rac1 deletion in mouse embryonic limb ectoderm causes limb truncation. However, the etiology of Rac1-associated cranial defects is unknown. To investigate the cranial defects, we used Pdgfra-Cre to delete Rac1 in cranial mesenchyme. Rac1-KO mice died perinatally and lacked the apical calvarium and overlying dermis, resembling defects seen in severe AOS. In control embryos, α-smooth muscle actin (αSMA) expression was spatially restricted to the apical mesenchyme, suggesting mechanical interactions between the growing brain and the overlying mesenchyme. In Rac1-KO embryos, proliferation of apical mesenchyme, and expression of αSMA and its regulator, serum response factor (SRF), were reduced. Remarkably, Srf-KO with Pdgfra-Cre recapitulated the phenotype observed in Rac1-KO mice. Together, these data suggest a model where Rac1 and SRF maintain apical fibroblasts in a mechanoresponsive and proliferative state to complete cranial development.