Coordination of projection neuron fate and position by let-7

项目总结： 中枢神经系统包含无数不同类型的细胞，它们接受和整合来自 以产生适当的生物反应的环境。未能生产出正确的成分 神经元亚型或其定位缺陷可导致多种精神和生理状况 从认知障碍到严重的脑畸形。在新大脑皮层，一个专门的多能细胞池 --被称为放射状神经胶质细胞--以一种保守的顺序产生所有不同的投射神经元群体。 重要的是，早期出生的投射神经元位于皮质板的顶侧，而较晚出生的神经元位于皮质板的顶侧 神经元位于它们的前驱细胞的顶部。尽管投射神经元的命运之间有很强的相关性 尽管这种相关性涉及的分子机制仍不明确，但其身份和位置尚不清楚。MicroRNAs (MiRNAs)最近被发现是强大的细胞命运决定因素，我们和其他人已经证明 LET-7在放射状胶质细胞中的表达促进晚出生皮质投射神经元的神经发生。 重要的是，我们进一步证明let-7的表达与脑内投射神经元的位置呈正相关。 上皮质层(即更靠近软膜表面)。我们的初步数据显示，let-7对神经元具有调节作用 通过反对E3泛素连接酶CRL5的核心成员Rbx2的表达而进行的迁移 被认为是结束投射神经元迁移的关键因素。因此，我们假设上调的基因表达 晚生投射神经元中的let-7降低CRL5的活性，促进神经元迁移。建议数 研究将确定let-7是神经前体能力和投射神经元的第一协调者 迁移/定位，并揭示其分子作用机制。

Project Summary: The central nervous system contains a myriad of different cell types that receive and integrate information from the environment to generate the appropriate biological responses. Failure to produce the right composition of neuronal subtypes or defects in their localization can result in several mental and physical conditions that range from cognitive disorders to severe brain malformations. In the neocortex, a specialized pool of multipotent cells -called radial glial cells- gives rise to all the different populations of projection neurons in a conserved sequence. Importantly, early born projections neurons localize at the apical side of the cortical plate whereas later born neurons localize atop of their predecessors. Despite the strong correlation between projection neuron fate identity and position, the molecular mechanisms involved in such correlation remain elusive. MicroRNAs (miRNAs) have recently been uncovered as strong cell fate determinants and we and others have shown that let-7 expression in radial glia cells promotes the neurogenesis of late born cortical projection neurons. Importantly, we further demonstrate that let-7 expression positive correlates with projection neuron location in upper cortical layers (i.e., closer to the pial surface). Our preliminary data show that let-7 regulates neuron migration by opposing the expression of Rbx2, a core member of the E3 ubiquitin ligase CRL5, previously identified as a key factor to end projection neuron migration. Thus, we hypothesize that elevated expression of let-7 in late-born projection neurons reduces the activity of CRL5, promoting neuron migration. The proposed research will identify let-7 as the first coordinator of neural progenitor competence and projection neuron migration/localization, and unveil its molecular mechanism of action.