Dchs1-fat4 regulation of osteogenic differentiation in mouse

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

doi:10.1242/dev.176776

Dchs1-fat4 regulation of osteogenic differentiation in mouse

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

Centre for Craniofacial & Regenerative Biology

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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.

Original language	English
Article number	dev176776
Journal	Development (Cambridge)
Volume	146
Issue number	14
Early online date	29 Jul 2019
DOIs	https://doi.org/10.1242/dev.176776
Publication status	Published - Jul 2019

Keywords

Dchs1-Fat4
Osteoblast
Runx2
Yap/Taz

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Dchs1-Fat4 regulation of_CRESPO-ENRIQUEZ_Accpeted20June2019Publishedonline29July2019_GREEN VoRFinal published version, 13.6 MB

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title = "Dchs1-fat4 regulation of osteogenic differentiation in mouse",

abstract = "Mutations of the protocadherins, FAT4 and DCHS1, result in Van Maldergem{\textquoteright}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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author = "Ivan Crespo-Enriquez and Tina Hodgson and Sana Zakaria and Erika Cadoni and Mittal Shah and Stephen Allen and Ayman Al-Khishali and Yaopan Mao and Angela Yiu and Jonna Petzold and Guillermo Villagomez-Olea and Pitsillides, {Andrew A.} and Irvine, {Kenneth D.} and Philippa Francis-West",

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AU - Hodgson, Tina

AU - Zakaria, Sana

AU - Cadoni, Erika

AU - Shah, Mittal

AU - Allen, Stephen

AU - Al-Khishali, Ayman

AU - Mao, Yaopan

AU - Yiu, Angela

AU - Petzold, Jonna

AU - Villagomez-Olea, Guillermo

AU - Pitsillides, Andrew A.

AU - Irvine, Kenneth D.

AU - Francis-West, Philippa

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AB - 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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Dchs1-fat4 regulation of osteogenic differentiation in mouse

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