内化接头蛋白HIP1R介导神经元树突生长和分支的作用及其机制研究

神经元树突形态发生是一个复杂精细的细胞生物学过程，正常的树突形态与神经环路装配和功能密切相关，而树突发育缺陷则多种神经和精神发育障碍的原因，因此阐明其分子细胞机制具有重要的生理和病理意义。亨廷顿蛋白互作蛋白1相关蛋白（HIP1R）是内吞接头蛋白，其基本功能是参与受体内化和稳定细胞骨架等，但在神经系统作用知之甚少。我们的研究表明，敲减HIP1R抑制神经元树突的生长和分支以及兴奋性突触形成，并提示还抑制了EGFR的内化，但机制有待阐明。本项目拟明确HIP1R与EGFR的相互作用，鉴定HIP1R的结合功能区，揭示HIP1R通过介导EGFR内吞及激活下游信号通路调节神经元树突发育的关键机制，并in vivo验证HIP1R的这一功能及行为学后果。该研究将揭示多功能内吞接头蛋白HIP1R在神经系统的基本功能，并加深对EGFR信号通路参与神经发育具体机制的认识。

Morphogenesis of neuronal dendrites is a complex, refined and ordered process that closely related to the assembly and function of neural circuit. A variety of neurological and mental development disorders are due to defects in dendritic development. Therefore, elucidating the molecular cellular mechanism is of great significance in physiology and pathology. Huntingtin-interacting protein 1-related protein (HIP1R), as an endocytic adapter protein, is involved in functions such as receptor internalization and stabilization of cytoskeletal structures. However, its role in central nervous system is still unclear. Our previous work has shown that knockdown HIP1R in developing neurons leads to a decreased dendritic growth and branching, impaired excitatory synapse function, as well as inhibition of activity induced internalization of EGFR. However, mechanism of these phenotypes remains unknown. This project aims to confirm the interaction between HIP1R and EGFR, to map the binding domain/site of HIP1R with EGFR, and to reveal the mechanism that HIP1R regulates the neuron dendritic development by mediating EGFR endocytosis and its downstream signaling. And we also plan to investigate in vivo HIP1R function and behavioral consequences in mice with hippocampal HIP1R knocking down. This study will reveal the basic function of endocytic adapter protein HIP1R in nervous system, and depended the insight into the critical role of EGFR signaling pathway in neural dendrite development.