Radial Glial Development And Differentiation

描述（由申请人提供）：放射状胶质细胞在哺乳动物大脑的构建中起着至关重要的作用，最初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性的支架，最终在成熟的大脑中促进星形胶质细胞谱系的形成。放射状胶质细胞的功能取决于这些细胞的结构和分子极性。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的异常位置和连接，这是许多发育性大脑疾病（如癫痫和精神分裂症）以及严重畸形(如小脑畸形（小脑）、脑裂畸形（大脑半球分裂）、无脑畸形（平滑的大脑，没有卷曲）、大脑回畸形（大卷曲）等的潜在原因。多小脑回（小脑卷）和结节性硬化症。本研究的目的是阐明在大脑皮层发育过程中，放射状胶质细胞如何分化为神经元前体、神经元迁移向导和星形胶质细胞前体的分子机制。

DESCRIPTION (provided by applicant): Radial glial cells play a critical role in the construction of the mammalian brain, initially, by functioning as a source of new neurons and by providing a permissive and instructive scaffold for neuronal migration, and eventually, by contributing to the formation of astroglial cell lineages in the mature brain. The function of radial glia depends on the structural and molecular polarity of these cells. Abnormalities in radial glial development, differentiation, and neuron- radial glial interactions lead to aberrant placement and connectivity of neurons in the human brain, an underlying cause of many developmental brain disorders such as epilepsy and schizophrenia, as well as of gross malformations such as microencephaly (small brain), schizencephaly (split brain hemispheres), lissencephaly (smooth cerebrum, without convolutions), macrogyria (large convolutions), polymicrogyria (small cerebral convolutions), and tuberous sclerosis. The aim of this proposal is to elucidate the molecular mechanisms that determine how radial glial cells differentiate to function as neuronal precursors, neuronal migratory guides, and as astrocyte precursors during cerebral cortical development. To examine the molecular signals regulating these processes, we have focused on neuregulin l (NRG1) and its receptors (erbB2, 3, and 4). Our earlier findings demonstrate that that NRG1 and its receptors play a crucial role in radial glial cell function in the developing cerebral cortex (Schmid et al., 2003). NRG1 promotes the establishment and differentiation of radial glia. In the absence of NRG1 signaling via erbB2 receptors, radial glial polarity and development is abnormal. Recently, NRG1 has been identified as a susceptibility gene for schizophrenia (Stefansson et al., 2002a; Stefansson et al., 2002b). Based on these findings, we hypothesize that the NRG1/erbB signaling plays an instructive role in radial glial cell development and differentiation. The proposed studies will test this hypothesis by analyzing (1) the role of NRGl-erbB2 interactions in the differentiation, polarity, and function of radial glial cells in cerebral cortex, and (2) whether radial glial identity can be regained in postnatal cerebral cortex through changes in NRG1- erbB2 signaling system. Together, these studies on radial glial development and differentiation will help in deciphering the basic mechanisms guiding normal cerebral cortical development as well as in unveiling the pathogenesis of various developmental brain disorders, including schizophrenia, where abnormal radial glial development and differentiation may result in defective cerebral cortical organization and thus in neurological functional deficits.