LINGO-1受体信号通路在皮层发育中的功能研究

皮层发育障碍是导致智力发育障碍和难治性癫痫的常见病因，发病原因复杂。LINGO-1/NgR1/p75(/TORY)是神经损伤修复中介导神经再生抑制信号的重要复合受体，然而皮层发育早期LINGO-1与其它共受体并不共存。体外研究提示其在神经干细胞发育中可能发挥重要功能，但具体机制还是空白，尚缺乏在体证据。在青年基金工作中我们发现LINGO-1通过结合并抑制WNK3进一步激活GSK3β活性的信号转到机制参与了神经元凋亡发生。而GSK3β信号在在皮层发育中发挥多重功能。我们将通过细胞，组织以及转基因动物多水平的研究揭示LINGO-1在皮层发育过程中对放射状胶质细胞的存活，分裂，形态维持以及神经前体细胞的存活、增殖、分化和迁移过程发挥何种功能，以及是否仍是通过与WNK3和GSK3β的功能耦联介导。本研究将为揭示LINGO-1在神经发育中的功能和机制提供在体研究证据，为皮层发育障碍的干预提供新的靶点

Malformations of cortical development (MCD) are common causes of neurodevelopmental delay and epilepsy, and a variety of factors and genes may be responsible for these disorders. Although LINGO-1/NgR1/p75(/TORY) is known for mediating inhibitory signaling during adult central nervous system injury, LINGO-1 and its co-receptors coexist in mouse brain in a defined time window only at later postnatal stages. In vitro evidence indicates that LINGO-1 play an important role in cultured stem cell during development, however the underlying mechanism is little and there is barely any in vivo evidence. In our previous work we identified a signaling pathway involved in promoting neuronal apoptosis that LINGO-1 interacts with and inhibits WNK3 kinase activity, which might further activate GSK3β. Given that GSK3β play multiple roles which are critical for normal cortical development, we would further explore for novel functions of LINGO-1 in radial glial cells‘s survival, cell division, polarity sustain and in daughter neuronal progenitors’ survival, division, proliferation and migration, as well as whether WNK3/GSK3β also served as the downstream signaling mechanism. This study would provide in vivo evidence for functions of LINGO-1 during cortical development, and novel targets for treatment of MCDs.