非典型钙黏蛋白Celsr1在小鼠大脑皮层发育中的功能和分子机制研究

在小鼠的大脑皮层发育过程中，神经干细胞能够产生大脑皮层中各种类型的神经细胞和神经胶质细胞，其自我更新和分化需要受到精细的调控。在神经发生过程中，神经干细胞不对称分裂的调控机制还不清楚，纺锤体的排列方式在神经干细胞的不对称分裂中的作用也存在很多的争议。本项目初步的研究结果发现，非典型钙黏蛋白Celsr1非常特异地在神经干细胞中表达，其成年突变体小鼠表现为“小脑症”，我们还发现在胚胎E14.5期Celsr1突变体中神经干细胞在有丝分裂期纺锤体的排列方式发生紊乱。本项目将深入研究Celsr1在小鼠大脑皮层发育中的作用，解析其调控纺锤体的排列的细胞学机制，并挖掘Celsr1的下游效应因子和与其有相互作用的蛋白/蛋白复合体从而阐明其分子机制。

During the corticogenesis of mouse, cortical neurons and glial cells are generated sequentially from neural stem cells (NSCs). The balance of self-renewal and differentiation of NSCs should be tuned precisely. However, the mechanisms of asymmetric cell division of NSCs during neurogenesis are still elusive. It is also controversial about the relationship between spindle orientation and NSCs asymmetric cell division. In our preliminary study, we find that Celsr1 is very specifically expressed in NSCs of the cortex and microcephaly is identified in the adult of Celsr1 mutant. And we also find that more mitotic spindles switch from horizontal to oblique and vertical in Celsr1 cortices at E14.5. In this project, we are going to decipher the mechanisms that how Celsr1 regulates the mitotic spindle orientation and mouse cortigogenesis, address the relationship between mitotic spindle orientation and microcephaly, and elucidate the downstream effectors of Celsr1 and proteins/protein complexes interacting with Ceslr1. These results will clarify the function of Celsr1 in mouse corticogenesis and shed new light on our understanding of microcephaly.