Radial Glial Development And Differentiation

描述(申请人提供)：放射状胶质细胞在哺乳动物大脑的构建中发挥关键作用，最初是作为新神经元的来源，并为神经元迁移提供允许和指导的支架，最终通过促进成熟大脑中星形胶质细胞系的形成而发挥作用。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位置和连接的异常，这是许多发育性脑疾病(如癫痫和精神分裂症)以及大体畸形的根本原因，如小脑(小脑)、裂脑(分裂的大脑半球)、无脑(光滑的大脑，没有卷曲)、大脑回(大的卷曲)、多小脑回(小的脑卷曲)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，放射状胶质细胞分化为神经元前体、神经元迁移导引和星形胶质细胞前体的分子机制。 为了研究调控这些过程的分子信号，我们重点研究了神经调节蛋白L(NRG1)及其受体(erbB_2、3和4)。我们早期的发现表明，NRG1及其受体在发育中的大脑皮层的放射状胶质细胞功能中起着至关重要的作用(Schmidet al.，2003)。NRG1促进放射状胶质细胞的建立和分化。在缺乏通过erbB2受体的NRG1信号的情况下，放射状胶质细胞的极性和发育是异常的。最近，NRG1已被确定为精神分裂症的易感基因(Stefansson等人，2002a；Stefansson等人，2002b)。基于这些发现，我们推测NRG1/erbB信号在放射状胶质细胞的发育和分化中起指导作用。这些研究将通过分析(1)NRG1-erbB2相互作用在大脑皮层放射状胶质细胞分化、极性和功能中的作用，以及(2)是否可以通过改变NRG1-erbB2信号系统在出生后大脑皮层重新获得放射状胶质细胞的同一性来验证这一假说。 总之，这些关于放射状胶质细胞发育和分化的研究将有助于破译引导大脑皮质正常发育的基本机制，并有助于揭示包括精神分裂症在内的各种发育性脑疾病的发病机制，在精神分裂症中，放射状胶质细胞发育和分化异常可能导致大脑皮质组织缺陷，从而导致神经功能障碍。

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.