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Dchs1-fat4 regulation of osteogenic differentiation in mouse

Research output: Contribution to journalArticle

Ivan Crespo-Enriquez, Tina Hodgson, Sana Zakaria, Erika Cadoni, Mittal Shah, Stephen Allen, Ayman Al-Khishali, Yaopan Mao, Angela Yiu, Jonna Petzold, Guillermo Villagomez-Olea, Andrew A. Pitsillides, Kenneth D. Irvine, Philippa Francis-West

Original languageEnglish
Article numberdev176776
JournalDevelopment (Cambridge)
Volume146
Issue number14
Early online date29 Jul 2019
DOIs
Publication statusPublished - Jul 2019

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King's Authors

Abstract

Mutations of the protocadherins, FAT4 and DCHS1, result in Van Maldergem’s syndrome characterized, in part, by craniofacial abnormalities. Here we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation. We show that Fat4 and Dchs1 mutants mimic the craniofacial phenotype of the human syndrome and that Dchs1-Fat4 signalling is essential for osteoblast differentiation. In Dchs1/Fat4 mutants, proliferation of osteoprogenitors is increased and osteoblast differentiation is delayed. We show that loss of Dchs1-Fat4 signalling is linked to increased Yap-Tead activity and that Yap is expressed and required for proliferation in osteoprogenitors. In contrast, Taz is expressed in more committed Runx2-expressing osteoblasts, Taz does not regulate osteoblast proliferation and Taz-Tead activity is unaffected in Dchs1/Fat4 mutants. Finally, we show that Yap and Taz differentially regulate the transcriptional activity of Runx2, and that the activity of Yap-Runx2 and that Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a new signaling pathway in osteoblast differentiation, reveal its critical role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.

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