Mechanisms of Forebrain Development

前脑发育机制

• 批准号: 7144801
• 负责人: ELIZABETH M POWELL
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144801
• 关键词: cell proliferation; hepatocyte growth factor; interneurons; neurons; receptor; role

DESCRIPTION (provided by applicant): Neuronal development in the central nervous system is the summation of multiple processes including cellular proliferation, migration, and differentiation. The hepatocyte growth factor/scatter factor (HGF/SF) signaling system via its receptor, MET, possesses multiple activities in cellular proliferation, migration, differentiation and survival. Initial studies demonstrated HGF/SF as a key molecule for cellular migration in the ventral forebrain. New data suggest a role in cell proliferation or survival. Genetically altered mice with reduced HGF/SF-MET signaling levels demonstrate reduced numbers of striatal GABA+ neurons and abnormal behavior. The behavioral phenotype is similar to observations from children afflicted fetal alcohol syndrome, including anxiety, social dysfunction and seizure disorders. Alcohol downregulates HGF/SF levels in many tissues, and exogenous HGF/SF can rescue the signaling deficits. These data suggest that the HGF/SF-MET system is an excellent model for defining the molecular mechanisms underlying the fetal response to alcohol exposure. We will examine the role of the HGF/SF-MET system in three aims: In Aim 1, we will define the role of HGF/SF in cell proliferation and survival. In Aim 2, we will investigate the specific actions of HGF/SF-MET system on migrating postmitotic cells. In Aim 3, we will determine how loss of HGF/SF responsiveness alters phenotypic expression of GABAergic markers. Defining the molecular mechanisms involved in the development of limbic structures is critical to our understanding of the behavioral and neurochemical alterations that result from prenatal drug exposure.

描述（由申请人提供）：中枢神经系统中的神经元发育是包括细胞增殖、迁移和分化在内的多个过程的总和。肝细胞生长因子/分散因子（HGF/SF）信号系统通过其受体MET，在细胞增殖、迁移、分化和存活中具有多种活性。初步研究表明 HGF/SF 是腹侧前脑细胞迁移的关键分子。新数据表明其在细胞增殖或存活中发挥作用。 HGF/SF-MET 信号水平降低的基因改造小鼠表现出纹状体 GABA+ 神经元数量减少和异常行为。行为表型与患有胎儿酒精综合症的儿童的观察结果相似，包括焦虑、社交功能障碍和癫痫症。酒精会下调许多组织中的 HGF/SF 水平，外源性 HGF/SF 可以挽救信号传导缺陷。这些数据表明 HGF/SF-MET 系统是定义胎儿对酒精暴露反应的分子机制的绝佳模型。我们将研究 HGF/SF-MET 系统在三个目标中的作用：在目标 1 中，我们将定义 HGF/SF 在细胞增殖和存活中的作用。在目标 2 中，我们将研究 HGF/SF-MET 系统对有丝分裂后细胞迁移的具体作用。在目标 3 中，我们将确定 HGF/SF 反应性的丧失如何改变 GABA 能标记的表型表达。定义边缘结构发育所涉及的分子机制对于我们理解产前药物暴露引起的行为和神经化学变化至关重要。