Mechanisms of Forebrain Development

前脑发育机制

• 批准号: 7275933
• 负责人: ELIZABETH M POWELL
• 金额: $ 28.84万
• 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/7275933
• 关键词: Address; Adult; Albumins; Alcohols; Anxiety; Area; Behavior; Behavioral; Biological; Cell Count; Cell Proliferation; Cells; Cerebral cortex; Child; Competence; Corpus striatum structure; Data; Development; Disruption; Embryo; Embryonic Development; Epilepsy; Event; Fetal Alcohol Syndrome; Forebrain Development; Functional disorder; Genetic Recombination; Goals; Hepatocyte Growth Factor; Immigration; Immunohistochemistry; In Situ Hybridization; Interneurons; Lead; Ligands; Limbic System; Location; Mantle Zone; Mediating; Mediator of activation protein; Mitogens; Modeling; Molecular; Mus; Mutant Strains Mice; Neuraxis; Neurons; Numbers; Pan Genus; Parvalbumins; Pattern; Phenotype; Population; Process; Prosencephalon; Protein Overexpression; Research Personnel; Role; Seizures; Signal Transduction; Slice; Source; Staging; Structure; System; Techniques; Technology; Telencephalon; Testing; Tissues; Transgenic Mice; Ventricular; alcohol response; cell motility; design; fetal; fetal drug exposure; gain of function; gamma-Aminobutyric Acid; loss of function; loss of function mutation; migration; neurochemistry; neuronal survival; postnatal; prenatal; progenitor; programs; receptor; relating to nervous system; research study; response; social

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/散射因子（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。最初的研究表明HGF/SF是腹侧前脑细胞迁移的关键分子。新的数据表明在细胞增殖或存活中的作用。具有降低的HGF/SF-MET信号传导水平的基因改变的小鼠表现出纹状体GABA+神经元数量减少和行为异常。行为表型与患有胎儿酒精综合征的儿童的观察结果相似，包括焦虑，社会功能障碍和癫痫发作。酒精在许多组织中下调HGF/SF水平，外源性HGF/SF可以挽救信号转导缺陷。这些数据表明，HGF/SF-MET系统是一个很好的模型，用于定义胎儿对酒精暴露的反应的分子机制。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。目的2：研究HGF/SF-MET系统对有丝分裂后迁移细胞的特异性作用。在目标3中，我们将确定HGF/SF反应性的丧失如何改变GABA能标记物的表型表达。定义参与边缘系统结构发育的分子机制对于我们理解产前药物暴露导致的行为和神经化学改变至关重要。