MOLECULAR BASIS OF NEURON/GILA INTERACTIONS IN THE CNS

神经元-神经胶质细胞的相互作用在脑胶质瘤的形成过程中起着关键作用。 中枢神经系统。神经胶质细胞提供了一条途径 有丝分裂后神经元从生发层迁移出去。 神经元影响细胞的增殖、存活和分化 神经胶质细胞。多项研究表明，神经胶质细胞和 神经源性因子在神经元和神经胶质细胞中发挥关键作用 前体的增殖和分化，但有关 这些信号的性质仍然很少。的长期目标 建议的研究是为了了解分子机制。 在发育中的哺乳动物中控制神经元-神经胶质细胞的相互作用 大脑。我们正在研究一种新的生长因子家族， 神经调节蛋白，它似乎牵涉到介导神经元- 外周和中枢神经系统中的神经胶质细胞相互作用。我们 现在有证据表明，神经调节蛋白可能在 发育中的小脑中神经元-神经胶质细胞的相互作用。我们有 研究表明，神经调节蛋白受体ERBB4在放射状细胞中表达 这些神经元在其上迁移的神经胶质纤维。的表达方式 这些分子在发育过程中受到调节，并被限制在 颗粒细胞移行期。我们也证明了 1)培养的小脑星形胶质细胞表达ERBB4，2)胶质细胞表达ERBB4 表达受细胞外信号的调节，3)神经胶质细胞 对神经调节蛋白刺激的反应与它们对刺激的反应相同 与神经元接触。这些观察结果表明，中性调节蛋白 可能介导颗粒细胞和Bergmann胶质细胞之间的相互作用， 这些相互作用可能对颗粒细胞很重要 迁移。这里提出的工作是为了阐明 中性粒细胞在中枢发育过程中的调节和作用 神经系统。拟议研究的具体目标是：1) 鉴定调控erbB表达的信号细胞 小脑星形胶质细胞中的受体；2)确定 NRG对Bergmann神经胶质细胞生物学的影响 NRG在颗粒神经元对胶质细胞影响中的作用 3)确定NRG在颗粒细胞迁移中的作用。 我们将研究神经调节蛋白在小脑颗粒细胞中的作用- 佛手胶在细胞和分子水平上的体外相互作用 技巧。神经调节蛋白受体具有广泛的正常范围 生物学作用，但也是原癌基因。因此，它是 很可能是任一种配体的功能或表达的改变 或受体，将参与导致 到癌症、智力低下、癫痫等中枢和 周围神经系统疾病。

Neuron-glia interactions play a critical role during the formation of the central nervous system. Glial cells provide the pathway for the migration of postmitotic neurons away from the germinal layers. Neurons influence the proliferation, survival and differentiation of glial cells. A variety of studies have demonstrated that glia and neuronal-derived factors play critical roles in neuronal and glia precursor proliferation and differentiation, but information abut the nature of these signals remains scarce. The long range objective of the proposed research is to understand the molecular mechanisms controlling neuron-glia interactions in the developing mammalian brain. We are studying a new family of growth factors, the neuregulins, which appears to be implicated in mediating neuron- glia interactions in the peripheral and central nervous system. We now have evidence suggesting that neuregulins may play a role in neuron-glia interactions in the developing cerebellum. We have shown that neuregulin receptors, erbB4, is expressed in the radial glial fibers over which these neurons migrate. The expression of these molecules is developmentally regulated, and restricted to the period of granule cell migration. We have also demonstrated that 1) cerebellar astroglia in culture express erbB4, 2) glial erbB4 expression is regulated by extracellular signals, and 3) glial cells response to neuregulin stimulation in the same manner they respond to contact with neurons. These observations suggest that neuregulin may mediate interactions between granule cells and Bergmann glia, and that these interactions may be important for granule cell migration. The work proposed here is directed to elucidate the regulation and functions of neuregulines in the developing central nervous system. The specific aims of the proposed research are: 1) To identify signals cells that regulate the expression of erbB receptors in cerebellar astroglial cells; 2) To determine effects of NRG on Bergmann glial cell biology, and to determine the contribution of NRG to the effects of granule neurons on the glial cells; 3) To determine the role of NRG in granule cell migration. We will study the role of neuregulin in cerebellar granule cell - Bergamann glia interactions in vitro using cellular and molecular techniques. Neuregulin receptors have a wide range of normal biological actions, but are also proto-oncogenes. Therefore, it is likely that alteractions in the function or expression of either ligand or receptors, will be involved in developmental processes that lead to cancer, mental retardation, epilepsy and other central and peripheral nervous system diseases.