Embryonic requirements for Tcf12 in the development of the mouse coronal suture

A major feature of Saethre-Chotzen syndrome is coronal craniosynostosis, the fusion of the frontal and parietal bones at the coronal suture. It is caused by heterozygous loss-of-function mutations in the basic HLH transcription factors TWIST1 and TCF12. While compound heterozygous Tcf12; Twist1 mice display severe coronal synostosis, the individual role of Tcf12 has remained unexplored. Here we show that Tcf12 controls several key processes in calvarial development, including the rate of frontal and parietal bone growth, and the boundary between sutural and osteogenic cells. Genetic analysis supports an embryonic requirement for Tcf12 in suture formation, as combined deletion of Tcf12 in the embryonic neural crest and mesoderm, but not in the postnatal suture mesenchyme, disrupts the coronal suture. We also detect asymmetric distribution of Grem1 + mesenchymal cells on opposing sides of the wild-type frontal and parietal bones, which prefigures later bone overlap at the sutures. In Tcf12 mutants, reduced asymmetry correlates with lack of bone overlap. Our results indicate a largely embryonic function of Tcf12 in controlling the rate and asymmetrical growth of calvarial bones and establishment of suture boundaries, which together ensure the proper formation of the overlapping coronal suture.