Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1

Adrian On Wah Leung, Andrew Chung Hin Poon, Xue Wang, Chen Feng, Peikai Chen, Zhengfan Zheng, Michael KaiTsun To, Wilson Cheuk Wing Chan (), Martin Cheung and Danny Chan ()
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Adrian On Wah Leung: The University of Hong Kong
Andrew Chung Hin Poon: The University of Hong Kong
Xue Wang: The University of Hong Kong
Chen Feng: The University of Hong Kong
Peikai Chen: The University of Hong Kong
Zhengfan Zheng: The University of Hong Kong
Michael KaiTsun To: The University of Hong Kong -Shenzhen Hospital (HKU-SZH)
Wilson Cheuk Wing Chan: The University of Hong Kong
Martin Cheung: The University of Hong Kong
Danny Chan: The University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Apoptosis occurs during development when a separation of tissues is needed. Synovial joint formation is initiated at the presumptive site (interzone) within a cartilage anlagen, with changes in cellular differentiation leading to cavitation and tissue separation. Apoptosis has been detected in phalangeal joints during development, but its role and regulation have not been defined. Here, we use a mouse model of brachydactyly type A1 (BDA1) with an IhhE95K mutation, to show that a missing middle phalangeal bone is due to the failure of the developing joint to cavitate, associated with reduced apoptosis, and a joint is not formed. We showed an intricate relationship between IHH and interacting partners, CDON and GAS1, in the interzone that regulates apoptosis. We propose a model in which CDON/GAS1 may act as dependence receptors in this context. Normally, the IHH level is low at the center of the interzone, enabling the “ligand-free” CDON/GAS1 to activate cell death for cavitation. In BDA1, a high concentration of IHH suppresses apoptosis. Our findings provided new insights into the role of IHH and CDON in joint formation, with relevance to hedgehog signaling in developmental biology and diseases.

Date: 2024
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DOI: 10.1038/s41467-024-45053-0

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