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谱系的形成。放射状胶质细胞发育、分化和神经元-放射状胶质细胞相互作用的异常导致人脑中神经元和胶质细胞的异常生成、位置和连接，这是许多发育性大脑疾病，如精神分裂症，以及伴随智力低下和癫痫障碍的严重脑畸形的根本原因(Marin和Rubinstein，2003；Ayala等人，2008；Ghashghaei等人，2008)。这一建议的目的是阐明调节放射状胶质细胞极性的分子机制，以及放射状胶质细胞极性如何转化为不同的放射状胶质细胞功能。我们的初步结果表明，腺瘤性息肉病结肠(APC)在脑发育过程中极化放射状神经胶质支架的发育过程中起着重要作用。因此，APC信号提供了一个独特的途径来研究决定放射状祖细胞极性及其对大脑皮层形成的贡献的机制。使用APC信号作为分子模型来分析这些过程，由于APC突变在智力低下、自闭症和脑瘤中的已知影响，假定了额外的意义(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是放射状胶质细胞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。这些研究将通过检验以下三个相关问题来验证这一假说：(1)APC在放射状胶质细胞极性的出现和维持以及由此产生的大脑皮层的形成中起什么作用？(2)APC在放射状胶质前体细胞中介导APC功能的信号通路是什么？(3)APC在放射状胶质细胞神经元后代中的作用是什么？总之，这些研究将极大地促进我们对放射状祖细胞及其衍生物在大脑皮层出现中所起作用的理解。此外，阐明APC信号在大脑皮层形成中的作用将有助于阐明神经发育性脑疾病和脑肿瘤发生的生物学基础。 公共卫生相关性：公共卫生相关性声明放射状祖细胞发育、分化和神经元-放射状胶质细胞相互作用的异常导致人脑中神经元的异常生成、放置和连接，这是许多发育性大脑疾病，如精神分裂症和脑严重畸形的根本原因，如无脑畸形、多小脑回和异位症(Marin和Rubinstein，2003；Ayala等人，2008；Ghashghaei等人，2008)。对控制放射状祖细胞及其后代的极性和分化的信号机制的描述，将极大地促进我们对放射状祖细胞及其衍生物在大脑皮层的出现和维持中所扮演的角色的理解。在这些研究中使用APC信号作为分子模型具有显著的额外的人类健康相关性，因为APC基因的胚系突变导致家族性腺瘤性息肉病(FAP)(Kinzler等人，1991)。APC在大脑皮层发育中的重要性在最近的研究中显而易见，该研究表明APC突变在人类中会导致脑肿瘤息肉病(Attard等人，2007年)。精神发育迟滞或自闭症在APC基因突变的个体中也很明显(Barber等人，1994；Finch等人，2005)。因此，阐明APC信号在放射状祖细胞及其衍生物中的作用，将有助于破译指导正常大脑皮层发育的基本机制，并有助于揭示各种发育性脑疾病的发病机制。

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. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Abnormalities in radial progenitor development, differentiation, and neuron- radial glial interactions lead to aberrant generation, placement and connectivity of neurons in human brain, an underlying cause of many developmental brain disorders such as schizophrenia, and gross brain malformations, such as lissencephaly, polymicrogyria, and heterotopias (reviewed in Marin and Rubinstein, 2003; Ayala et al., 2008; Ghashghaei et al., 2008). Characterization of signaling mechanisms controlling the polarity and differentiation of radial progenitors and their progeny, as outlined in this proposal, will significantly advance our understanding of the role radial progenitors and their derivatives play in the emergence and maintenance of the cerebral cortex. The use of APC signalling as a molecular model in these studies has significant additional human health relevance since germ-line mutations of the APC gene results in familial adenomatous polyposis (FAP) (Kinzler et al., 1991). The significance of APC in cerebral cortical development is evident in recent studies demonstrating that APC mutations in humans cause brain tumor polyposis (Attard et al., 2007). Mental retardation or autism is also evident in individuals with APC mutations (Barber et al., 1994; Finch et al., 2005). Therefore, elucidating the role of APC signalling in radial progenitors and their derivatives will help in deciphering the basic mechanisms guiding normal cerebral cortical development as well as in unveiling the pathogenesis of various developmental brain disorders.