Molecular mechanism of Hedgehog signal transduction

Hhedgehog(HH)信号是动物的一条主要发育途径。在腹侧神经管构型中，Sonic hedgehog(Shh)作为一种形态原，编程在特定的背腹位置形成不同类型的细胞。分级Shh信号如何有助于明确不同的细胞命运，在分子方面还知之甚少。我的实验室一直在研究HH信号转导的分子机制。我们发现有三种Gli蛋白在小鼠体内作为HH信号的转录激活和/或抑制因子发挥作用。我们还发现Kif7和Sufu是Gli激活物和抑制物的关键调节者，它们在腹侧神经管模式形成过程中合作定义分级的HH信号。初级纤毛是HH信号转导所必需的微管细胞器。在途径激活后，Kif7与Gli蛋白相互作用，共同运输到纤毛，然后Kif7促进细胞质Gli-Sufu复合体的解离，导致Gli激活剂的核转位。然而，这些事件背后的分子机制仍然难以捉摸。

Hedgehog (Hh) signalling is a major developmental pathway in animals. In ventral neural tube patterning, Sonic hedgehog (Shh) acts as a morphogen programming the formation of diverse cell types at specific dorsoventral positions. How graded Shh signalling contributes to the specification of distinct cell fates is poorly understood in molecular terms. My laboratory has been studying the molecular mechanism of Hh signal transduction. We showed that three Gli proteins function as transcriptional activator and/or repressor of Hh signalling in mice. We also identified Kif7 and Sufu as key regulators of both Gli activators and repressors, and that they cooperate to define graded Hh signalling during ventral neural tube patterning. Primary cilia are microtubule-based organelles essential for Hh signal transduction. Upon pathway activation, Kif7 interacts with Gli proteins and together they traffic to the cilia, and then Kif7 promotes the dissociation of cytoplasmic Gli-Sufu complexes, resulting in nuclear translocation of Gli activator. However, the molecular mechanism underlying these events remains elusive.