DSCAM regulates delamination of neurons in the developing midbrain
DSCAM regulates delamination of neurons in the developing midbrain
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DOI：
10.1126/sciadv.aba1693
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
Hoshino, Mikio
中科院分区：
文献类型：
--
作者：
Arimura, Nariko;Okada, Mako;Hoshino, Mikio
为了正常的神经发生和神经回路形成，必须精确控制分化神经元与增殖区的分层；然而，细胞附着的调控机制尚不清楚。在这里，我们发现唐氏综合征细胞粘附分子（DSCAM）通过局部抑制中脑背端端足的RapGEF2-Rap1-N-cadherin级联来控制神经元分层。Dscam转录本在分化神经元中表达，Dscam蛋白在顶端终足的远端部分积累。基于cre - loxp的神经元标记显示，Dscam敲除会损害尾足与脑室的分离。DSCAM与RapGEF2结合使Rap1失活，而Rap1的活性是n -钙粘蛋白的膜定位所必需的。相应的，Dscam敲除增加了终足N-cadherin的定位和心室附着面积。此外，通过共同敲低RapGEF2或N-cadherin，可以恢复Dscam敲低导致的过度终足附着。我们的发现揭示了调控早期神经元发育关键步骤的分子机制。
For normal neurogenesis and circuit formation, delamination of differentiating neurons from the proliferative zone must be precisely controlled; however, the regulatory mechanisms underlying cell attachment are poorly understood. Here, we show that Down syndrome cell adhesion molecule (DSCAM) controls neuronal delamination by local suppression of the RapGEF2-Rap1-N-cadherin cascade at the apical endfeet in the dorsal midbrain. Dscam transcripts were expressed in differentiating neurons, and DSCAM protein accumulated at the distal part of the apical endfeet. Cre-loxP-based neuronal labeling revealed that Dscam knockdown impaired endfeet detachment from ventricles. DSCAM associated with RapGEF2 to inactivate Rap1, whose activity is required for membrane localization of N-cadherin. Correspondingly, Dscam knockdown increased N-cadherin localization and ventricular attachment area at the endfeet. Furthermore, excessive endfeet attachment by Dscam knockdown was restored by co-knockdown of RapGEF2 or N-cadherin. Our findings shed light on the molecular mechanism that regulates a critical step in early neuronal development.