Dchs1-Fat4 regulation of osteogenic differentiation in mouse

• DOI: 10.1242/dev.176776
• Publication Date: 2019-07-29T14:45:11Z
• Authors: Ivan Crespo-Enriquez; Tina Hodgson; Sana Zakaria; Erika Cadoni; Mittal Shah; Stephen Allen; Ayman Al-Khishali; Yaopan Mao; Angela Yiu; Jonna Petzold; Guillermo Villago...; Andrew A. Pitsill...; Kenneth D. Irvine; Philippa Francis-...
• Keywords: Joint Instability; 0301 basic medicine; 570; Foot Deformities, Congenital; 610; Mice, Transgenic; Craniofacial Abnormalities; Mice; 03 medical and health sciences; Runx2; Osteogenesis; Intellectual Disability; Animals; Humans; Abnormalities, Multiple; Cells, Cultured; 0303 health sciences; Osteoblasts; Osteoblast; Cell Differentiation; Cadherins; Embryo, Mammalian; Mice, Inbred C57BL; Disease Models, Animal; Animals, Newborn; Female; Hand Deformities, Congenital; Dchs1-Fat4; Yap/Taz

ABSTRACT In human, mutations of the protocadherins FAT4 and DCHS1 result in Van Maldergem syndrome, which is characterised, in part, by craniofacial abnormalities. Here, we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation in mouse. 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 Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a signalling pathway in osteoblast differentiation, reveal its crucial role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.