Transcriptional and epigenetic control of cranial bone lineage development

Abstract

During development, proper spatiotemporal patterning and specification of tissues requires precisely orchestrated changes in gene expression, which are regulated by transcription factors and epigenetic modification in response to instructive cues from cell signaling pathways. Development of the skull bones requires the coordination of two stem progenitor populations, the cranial neural crest cells (CNCC) and head paraxial mesoderm (PM), to ensure cell fate selection and morphogenesis. We previously demonstrated that Wnt/β‐catenin signaling acts as a molecular switch in the cranial mesenchyme by simultaneously specifying cranial bone and dermal lineages and repressing cartilage cell fate. We identified Wnt signaling and TWIST1 function in a feed‐forward loop to sustain Wnt signaling and promote the differentiation of calvarial bone progenitors. In order to understand the function of epigenetic mechanisms calvarial bone development at different developmental stages, we conditionally deleted Ezh2 which is part of the Polycomb Repressive Complex 2 in a stage‐specific manner in vivo. We found that Ezh2 is required early and transiently to promote bone progenitor commitment. Inhibition of retinoic acid (RA) signaling in Ezh2 mutants in vivo rescues calvarial bone development, and RA signaling activation in the conditional Ezh2 background leads to synergistic activation of anti‐osteogenic factors, such as Hand2 and HoxC8. Our results suggest that RA signaling and Ezh2 can function in parallel in an incoherent type1 feed forward loop to balance the suppression of anti‐osteogenic factors to permit later differentiation events in the calvarial bone lineage program. Our data provide new insights into the dynamic gene regulation during the specification of calvarial bones and commitment to intramembranous bone formation.Support or Funding InformationNIH‐NIDCR DE‐01870This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.