FGFR3经ICK-初级纤毛-IHH调节生长板发育的作用与机制研究

FGFR3可负性调节生长板中的IHH信号，在软骨生长板发育调控中发挥重要作用,但详细机制不清。我们发现模拟人FGFR3功能增强所致软骨发育不全(ACH)的小鼠的生长板软骨初级纤毛(PC)长度变短，IHH的共受体Smo在纤毛分布异常。同时，FGFR3可与调节纤毛的肠蛋白激酶(ICK)结合并影响其亚细胞分布。我们提出ACH为纤毛相关病变这一全新观点及如下分子机制：FGFR3通过与ICK结合，减少ICK胞核定位，导致PC形成及Smo-Gli复合物运输障碍，进而降低IHH活性，引起软骨发育障碍。本课题拟利用软骨（可诱导）增强/敲除FGFR3小鼠，通过表型分析及组织、细胞培养结合ICK、IHH相关干预，深入研究FGFR3经ICK调控PC及IHH信号的作用与机制。通过本研究可望明确FGFR3突变致ACH侏儒表型的新机制，为探索相关生物治疗措施提供实验基础，为纤毛相关遗传病的机制及治疗策略研究提供借鉴。

FGFR3 signaling plays critical roles in growth plate development. Several studies found that FGFR3 negative regulates IHH in growth plate, but the detailed mechanism is still not elucidated. Recently, we found that the lengths of primary cilia were significantly shorter in growth plates of ACH mice carrying FGFR3 gain-of-function (GOF) mutation at P3 and P5. We further, identified a well-established cilia regulator, intestinal cell kinase (ICK), can interact with FGFR3. FGFR3 signaling can trigger cytoplasmic accumulation of ICK. We propose a novel viewpoint that achondroplasia caused by FGFR3 GOF mutation is a ciliopathy. Our hypothesis is that FGFR3 may lead to cellular cilia disorder through its interactions with ICK, decreasing nucleus localization of ICK, then disturb the formation of cilia and intraflagellar transport of IHH-related molecules such as Smo-Gli complex. To reveal the detailed cellular and molecular mechanisms, we will combine mice with genetically modified FGFR3 in cartilage with tissue/cell culture and ICK, IHH related intervention in vitro to study the roles and mechanisms of FGFR3 in the regulation of growth plate development through primary cilia mediated IHH signaling. These studies will deepen our knowledge about the pathogenesis of FGFR3-related chondrodysplasia and ciliopathies, and provide experimental basis for the development of therapies for these diseases.