Wu Qinwei, Sun Xiaqin, Yue Weihua, Lu Tianlan, Ruan Yanyan, Chen Tianda, Zhang Dai
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Mol Brain. 2016 Feb 16;9:19. doi: 10.1186/s13041-016-0198-2.
Loss of function mutations in RAB18, has been identified in patients with the human neurological and developmental disorder Warburg Micro syndrome. However, the function of RAB18 in brain remains unknown.
In this study, we report that RAB18 is a critical regulator of neuronal migration and morphogenesis. Using in utero electroporation suppression of RAB18 in the mouse brain impairs radial migration. Overexpression of dominant negative RAB18 or disruption of RAB3GAP (RAB18GEF) also results in delayed neuronal migration in the developing mouse cortex and inhibition of neurite growth in vitro. Moreover, loss of RAB18 induces an acceleration of N-cadherin degradation by lysosomal pathway resulting in the decrease of surface level of N-cadherin on neurons.
RAB18 regulates neuronal migration and morphogenesis during development. Our findings highlight the critical role of RAB3GAP-RAB18 pathway in the developing cerebral cortex and might explain some of clinical features observed in patients with Warburg Micro syndrome.
在患有人类神经和发育障碍瓦尔堡微综合征的患者中已鉴定出RAB18的功能丧失突变。然而，RAB18在大脑中的功能仍然未知。
在本研究中，我们报告RAB18是神经元迁移和形态发生的关键调节因子。在小鼠脑中使用子宫内电穿孔抑制RAB18会损害放射状迁移。显性负性RAB18的过表达或RAB3GAP（RAB18鸟苷酸交换因子）的破坏也会导致发育中小鼠皮质中神经元迁移延迟和体外神经突生长受到抑制。此外，RAB18的缺失通过溶酶体途径诱导N-钙黏蛋白降解加速，导致神经元表面N-钙黏蛋白水平降低。
RAB18在发育过程中调节神经元迁移和形态发生。我们的研究结果突出了RAB3GAP-RAB18途径在发育中的大脑皮质中的关键作用，并可能解释了在瓦尔堡微综合征患者中观察到的一些临床特征。
