Radial Glial Development and Differentiation

描述（申请人提供）：极化的放射状胶质细胞为大脑皮层的形成提供了模板。最初，它们的功能是作为新神经元的来源，并为神经元迁移提供一个允许和指导的支架。随后，它们有助于成熟大脑中神经胶质细胞系的形成。放射状神经胶质发育、分化和神经元-放射状神经胶质相互作用的异常导致人类大脑中神经元和神经胶质的异常产生、位置和连接，这是许多发育性脑疾病的潜在原因，如精神分裂症，以及伴随智力迟钝和癫痫发作的严重脑畸形（Marin和Rubinstein, 2003； Ayala等，2008；Ghashghaei等，2008）。本研究的目的是阐明调节径向胶质细胞极性的分子机制，以及径向胶质细胞极性如何转化为不同的径向胶质细胞功能。我们的初步结果表明，在大脑发育过程中，大肠腺瘤性息肉病（APC）在极化放射状胶质支架的发育中起重要作用。因此，APC信号为研究决定径向祖细胞极性及其对大脑皮层形成的贡献的机制提供了一个独特的途径。使用APC信号作为分子模型对这些过程进行分析，由于已知APC突变在智力迟钝、自闭症和脑肿瘤中的作用，因此具有额外的意义（Attard等人，2007；Barber等人，1994；Finch等人，2005；Gsmez Garcma和Knoers， 2008）。基于这些发现，我们假设APC是放射状胶质极性不同方面的重要调节因子，对大脑皮层的构建至关重要。本研究将通过研究以下三个相关问题来验证这一假设：(1)APC在放射状胶质极性的出现和维持以及由此形成的大脑皮层中的作用是什么？2)在放射状胶质祖细胞中APC功能的信号通路是什么？(3) APC在放射状胶质细胞的神经子代中有何作用？总之，这些研究将显著促进我们对放射状祖细胞及其衍生物在大脑皮层出现中的作用的理解。此外，阐明APC信号在大脑皮层形成中的作用将有助于描述脑神经发育障碍和脑肿瘤发生的生物学基础。

DESCRIPTION (provided by applicant): Polarized radial glial cells provide a template for the formation of cerebral cortex. Initially, they function as a source of new neurons and provide a permissive and instructive scaffold for neuronal migration. Subsequently, they contribute to the formation of glial cell lineages in the mature brain. Abnormalities in radial glial development, differentiation, and neuron- radial glial interactions lead to aberrant generation, placement and connectivity of neurons and glia in human brain, an underlying cause of many developmental brain disorders such as schizophrenia, and gross brain malformations that accompanies mental retardation and seizure disorders (reviewed in Marin and Rubinstein, 2003; Ayala et al., 2008; Ghashghaei et al., 2008). The aims of this proposal are to elucidate the molecular mechanisms regulating the polarity of radial glia and how radial glial polarity is translated into distinct radial glial functions. Our preliminary results show that Adenomatous Polyposis Coli (APC) serves an essential function in the development of polarized radial glial scaffold during brain development. APC signalling thus provides a unique avenue to examine the mechanisms that determine radial progenitor polarity and its contribution to the formation of cerebral cortex. Analysis of these processes, using APC signalling as a molecular model, assumes additional significance due the known effects of APC mutations in mental retardation, autism, and brain tumors (Attard et al., 2007; Barber et al., 1994; Finch et al., 2005; Gsmez Garcma and Knoers, 2008). Based on these findings, we hypothesize that APC is an essential regulator of distinct aspects of radial glial polarity and is critical for the construction of cerebral cortex. The proposed studies will test this hypothesis by examining the following three related questions: (1) What is the role of APC in the emergence and maintenance of radial glial polarity and the resultant formation of cerebral cortex?, 2) What are the signaling pathways mediating APC function in radial glial progenitors?, and (3) What is the function of APC in neuronal progeny of radial glia? Together, these studies will significantly advance our understanding of the role radial progenitors and their derivatives play in the emergence of cerebral cortex. Further, elucidating the role of APC signalling in cerebral cortical formation will help to delineate the biological basis of neurodevelopmental brain disorders and brain tumorogenesis.