Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration
Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration
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DOI：
10.1038/nature09874
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发表时间：
2011-04-21
期刊：
影响因子：
64.8
通讯作者：
Acker-Palmer, Amparo
中科院分区：
文献类型：
--
作者：
Sentuerk, Aycan;Pfennig, Sylvia;Acker-Palmer, Amparo
发育中和成年大脑中神经元的协调迁移对其正常功能至关重要。分泌的糖蛋白Reelin（也称为Reelin N）通过结合两种脂蛋白受体（极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER 2，也称为LRP 8））来引导神经元迁移（1）。人类Reelin功能的丧失导致严重的发育障碍无脑畸形（2），并且它还与其他神经系统疾病如癫痫、精神分裂症和阿尔茨海默病（3）相关。Reelin激活其受体并控制细胞功能的分子机制在很大程度上是未知的。在这里，我们表明，神经元的指导线索肝配蛋白B蛋白是必不可少的Reelin信号在大脑中的分层结构的发展。我们表明，ephrin Bs基因相互作用与Reelin。值得注意的是，复合小鼠突变体（Reln（+/-）; Efnb 3（-/-）或Reln（+/-）; Efnb 2（-/-））和三重肝配蛋白B1、B2、B3敲除显示神经元迁移缺陷，其重现了在reeler小鼠的新皮质、海马和小脑中观察到的缺陷。从机制上讲，我们表明，Reelin结合到ephrin Bs的细胞外结构域，其在膜上与神经元中的VLDLR和ApoER 2相关联。肝配蛋白B的聚集导致Dab 1的募集和磷酸化，这是Reelin信号传导所必需的。相反，ephrin Bs功能的丧失严重损害了Reelin诱导的Dab 1磷酸化。重要的是，在不存在Reelin蛋白的情况下，Ephrin Bs的激活可以挽救reeler神经元迁移缺陷。总之，我们的研究结果确定ephrin Bs作为Reelin受体/信号通路的重要组成部分，以控制神经系统发育过程中的神经元迁移。
Coordinated migration of neurons in the developing and adult brain is essential for its proper function. The secreted glycoprotein Reelin (also known as RELN) guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, also known as LRP8)(1). Loss of Reelin function in humans results in the severe developmental disorder lissencephaly(2) and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer's disease(3). The molecular mechanisms by which Reelin activates its receptors and controls cellular functions are largely unknown. Here we show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. We show that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln(+/-); Efnb3(-/-) or Reln(+/-); Efnb2(-/-)) and triple ephrin B1, B2, B3 knockouts show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. Mechanistically, we show that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 which is necessary for Reelin signalling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Together, our results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system.