Mechanisms of Forebrain Development

前脑发育机制

• 批准号: 7634514
• 负责人: ELIZABETH M POWELL
• 金额: $ 28.26万
• 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/7634514
• 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; 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; Pan Genus; Parvalbumins; Pattern; Phenotype; Population; Process; Prosencephalon; 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; nerve stem cell; neurochemistry; neuron development; neuronal survival; overexpression; postnatal; prenatal; programs; receptor; research study; response; social; subventricular zone

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（申请人提供）：中枢神经系统的神经元发育是细胞增殖、迁移和分化等多个过程的总和。肝细胞生长因子/散点因子（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是前脑腹侧细胞迁移的关键分子。新的数据表明它在细胞增殖或存活中起作用。HGF/SF-MET信号水平降低的转基因小鼠表现出纹状体GABA+神经元数量减少和行为异常。行为表型类似于对胎儿酒精综合症患儿的观察，包括焦虑、社交功能障碍和癫痫。酒精下调许多组织中的HGF/SF水平，外源性HGF/SF可以挽救信号缺陷。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。我们将在三个目标中研究HGF/SF- met系统的作用：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Aim 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Aim 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。确定边缘结构发育的分子机制对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。