The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis

The murine Foxc1/Mf1 and Foxc2/Mfh1 genes encode closely related forkhead/w inged helix transcription factors with overlapping expression in the formin g somites and head mesoderm and endothelial and mesenchymal cells of the de veloping heart and blood vessels. Embryos lacking either Foxc1 or Foxc2, an d most compound heterozygotes, die pre- or perinatally with similar abnorma l phenotypes, including defects in the axial skeleton and cardiovascular sy stem. However, somites and major blood vessels do form. This suggested that the genes have similar, dose-dependent functions, and compensate for each other in the early development of the heart, blood vessels, and somites. In support of this hypothesis, we show here that compound Foxc1; Foxc2 homozy gotes die earlier and with much more severe defects than single homozygotes alone. Significantly, they have profound abnormalities in the first and se cond branchial arches, and the early remodeling of blood vessels. Moreover, they show a complete absence of segmented paraxial mesoderm, including ant erior somites. Analysis of compound homozygotes shows that Foxc1 and Foxc2 are both required for transcription in the anterior presomitic mesoderm of paraxis, Mesp1, Mesp2, Hes5, and Notch1, and for the formation of sharp bou ndaries of Dll1, Lfng, and ephrinB2 expression. We propose that the two gen es interact with the Notch signaling pathway and are required for the prepa tterning of anterior and posterior domains in the presumptive somites throu gh a putative Notch/Delta/Mesp regulatory loop.