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 Ihh^E95K 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.

当需要分离组织时，细胞凋亡发生在发育过程中。滑膜关节形成是在软骨原基内的假定部位（区间）开始的，细胞分化的变化导致空化和组织分离。在发育过程中，指骨关节中已检测到细胞凋亡，但其作用和调节尚未明确。在这里，我们使用具有 Ihh ^E95K突变的 A1 型短指畸形 (BDA1) 小鼠模型，以表明中指骨缺失是由于发育中的关节未能形成空洞，与细胞凋亡减少相关，而关节则不存在。形成。我们发现 IHH 与相互作用的伙伴 CDON 和 GAS1 在调节细胞凋亡的区域间存在着复杂的关系。我们提出了一个模型，其中 CDON/GAS1 可以在这种情况下充当依赖性受体。通常，区域间中心的 IHH 水平较低，使得“无配体”CDON/GAS1 能够激活空化细胞死亡。在 BDA1 中，高浓度的 IHH 会抑制细胞凋亡。我们的研究结果为 IHH 和 CDON 在关节形成中的作用提供了新的见解，并与发育生物学和疾病中的刺猬信号传导相关。