Stage-specific roles of Ezh2 and Retinoic acid signaling ensure calvarial bone lineage commitment

Developmental Biology
James W FergusonRadhika Atit

Abstract

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. The epigenetic methyltransferase, Ezh2, plays a role in skull bone formation, but the spatiotemporal function of Ezh2 between the CNCC- and PM-derived bone formation in vivo remains undefined. Here, using a temporally-inducible conditional deletion of Ezh2 in both the CNCC- and PM- derived cranial mesenchyme between E8.5 and E9.5, we find a reduction of the CNCC-derived calvarial bones and a near complete loss of the PM-derived calvarial bones due to an arrest in calvarial bone fate commitment. In contrast, deletion of Ezh2 after E9.5 permits PM-derived skull bone development, suggesting that Ezh2 is required early to guide calvarial bone progenitor commitment. Furthermore, exposure to all-trans Retinoic acid at E10.0 can mimic the Ezh2 mutant calvarial phenotype, and administration of the pan retinoic acid receptor (RAR) antagonist, BMS-453, to Ezh2 mutants partially restores the commitment to the calvarial bone lineage and PM-derived bone development in vivo. Exogenous RA signaling activation in the Ezh2 mutants lead...Continue Reading

Citations

Feb 26, 2019·Genesis : the Journal of Genetics and Development·Krishnakali Dasgupta, Juhee Jeong
Jun 4, 2019·Genesis : the Journal of Genetics and Development·Antionette L Williams, Brenda L Bohnsack
Jul 7, 2019·Nature Biomedical Engineering·Christina Jacobsen, April M Craft
Aug 5, 2020·Current Osteoporosis Reports·Timothy NehilaRadhika P Atit
May 12, 2021·Molecular and Cellular Biology·Angeliki VogiatziGeorge Mavrothalassitis

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