Mechanism and function of Lef1-mediated hypothalamic neurogenesis.

Lef1介导的下丘脑神经发生的机制和功能。

• 批准号: 10054036
• 负责人: RICHARD I DORSKY
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054036
• 关键词: Address; Adult; Anatomy; Animals; Anti-Anxiety Agents; Anxiety; Behavior; Behavioral; Binding; Biochemical Genetics; Biological Process; Brain; Brain region; Cell Transplantation; ChIP-seq; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Defect; Development; Disease; Embryonic Development; Endocrine system; Exhibits; Fishes; Genes; Genetic; Genetic Transcription; Goals; Hormones; Human; Hydrocortisone; Hypothalamic structure; Instinct; Laboratories; Lead; Life; Link; Mediating; Mediator of activation protein; Molecular; Mood Disorders; Neurons; Pathway interactions; Phenotype; Physiological; Pituitary Gland; Play; Population; Population Control; Posterior Hypothalamus; Process; Regulation; Role; Specific qualifier value; Stress; Structure; Testing; WNT Signaling Pathway; Work; Zebrafish; anxiety-like behavior; anxiety-related behavior; behavioral phenotyping; conditional knockout; experimental study; gene function; genetic manipulation; homologous recombination; insight; mutant; nerve stem cell; neurogenesis; novel; progenitor; self-renewal; tool; transcription factor; transcriptome sequencing

Project Summary The genetic and molecular mechanisms that establish innate behaviors across diverse species are largely unknown. We have discovered an evolutionarily conserved role for Lef1-mediated Wnt signaling in the regulation of anxiety and in the differentiation of anxiolytic neurons in the zebrafish posterior hypothalamus. However mechanistic links between Lef1 targets, neurogenesis, and neuronal function in behavior have not yet been established. We also know that new neurons are continually added to this brain region, but it is not clear whether they contribute to anxiety-related behavior. This proposal will test the hypothesis that Lef1-mediated target genes regulate hypothalamic neurogenesis to control anxiety-related behavior throughout life. Three specific aims will determine which Lef1 targets are required for the formation of anxiolytic neurons, whether those neurons regulate stress hormone levels through the HPI axis, and whether postembryonic Lef1-dependent neurogenesis can mediate behavior. Together this work will define a novel mechanism for the regulation of an innate behavior through neurogenesis.

项目摘要 在不同物种中建立先天行为的遗传和分子机制主要是 未知我们已经发现了Lef1介导的Wnt信号在调控中的进化保守作用， 的焦虑和分化的抗焦虑神经元在斑马鱼后下丘脑。然而 Lef1靶点、神经发生和行为中神经元功能之间的机制联系尚未被阐明。 确立了习我们还知道，新的神经元不断添加到这个大脑区域，但不清楚是否 它们会导致焦虑相关的行为。这一提议将检验Lef1介导的靶基因 调节下丘脑神经发生以控制一生中与焦虑相关的行为。三个具体目标将 确定哪些Lef1靶点是形成抗焦虑神经元所必需的，这些神经元是否调节 通过HPI轴的应激激素水平，以及胚后Lef1依赖的神经发生是否可以 调解行为。这项工作将共同定义一种调节先天行为的新机制 通过神经发生。