Cellular differentiation in the developing preoptic area

视前区发育中的细胞分化

基本信息

批准号：
7798591
负责人：
STUART A. TOBET
金额：
$ 29.58万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-10 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7798591
关键词：
Accounting Address Adrenal Glands Adrenal gland hypofunction Adult Affect Age Agonist Aldehydes Androgens Animals Anterior Hypothalamus Anxiety Behavior Behavioral Body Weight Brain Brain region Calcium-Binding Proteins Cell Death Cell Differentiation process Cells Characteristics Data Dependence Development Developmental Process Embryo Enzyme Inhibitor Drugs Enzyme Inhibitors Epigenetic Process Estrogen Receptors Estrogens Evaluation Exposure to FOS gene Female Fetal Development Fluorescence Gene Expression Generations Genes Genetic Goals Gonadal Steroid Hormones Gonadal structure Home environment Hormonal Hormones Hypothalamic structure In Situ Hybridization In Vitro Instruction Knock-out Knockout Mice Label Lead Life Mammalian Cell Mental disorders Methods Modeling Movement Mus Neonatal Neurosecretory Systems Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Type I Output Phase Phenotype Physiology Population Positioning Attribute Predisposition Preoptic Areas Procedures Process Progesterone Proteins Role SF1 Sex Characteristics Signal Transduction Slice Social Behavior Steroid Receptors Steroids Structure Testing Time Transgenic Mice Transgenic Organisms Transplantation Video Microscopy Y Chromosome behavior test calbindin cell motility fetal immunocytochemistry in vitro testing in vivo indexing male mature animal migration mouse steroidogenic factor 1 prevent promoter protein expression relating to nervous system sex steroid hormone

项目摘要

DESCRIPTION (provided by applicant): Sex differences in the cellular differentiation of the developing brain when paired with altered development can lead to abnormal circuitries that may be associated with sex differences in susceptibility to major mental disorders. The goal of our studies is to determine where and how genetic and hormonal factors interact to result in sexual differentiation of the brain. This proposal concentrates on the formation of the preoptic area/ anterior hypothalamus (POA/AH) as a key target for studying this process. The POA/AH is important for regulating homeostatic, neuroendocrine, and behavioral functions. It is a region where hormones dramatically influence development and where hormone-concentrating cells regulate physiology and behavior. We hypothesize that gonadal steroid hormones may "overwrite" direct genetic instructions, and a hormone-free development allows evaluation of the underlying genetic instructions. Mice with a disrupted steroidogenic factor-1 (SF-1) gene never develop a gonad and provide a model to test the hormone- dependence versus independence of selected characteristics of brain sexual differentiation. Our methods render developmental processes accessible to live observation, and direct manipulation in vitro. We can raise SF-1 knockout (KO) mice to adulthood to assess adult consequences of brain sexual differentiation without endogenous gonadal steroids. Three major questions will be addressed: 1) How are sex differences in the positioning of cells in the embryonic POA/AH regulated by gonadal steroids at different ages? 2) Does nitric oxide generation contribute to the development of the POA/AH by influencing the characteristics of cell migration, cell death, or the phenotypic differentiation of cells? 3) What are the functional consequences of developing in the absence of exposure to gonadal steroids? These questions will be addressed using unique transgenic and gene disrupted models that mark specific cell populations for fluorescence and prevent endogenous gonadal steroid hormone synthesis or prevent neural generation of nitric oxide. The proposed studies will bring us closer to determining the hormone-dependent and independent steps involved in the establishment of sex differences in brain structure and function.

描述（由申请人提供）：与发育发生变化时，发育中大脑细胞分化的性别差异可能导致异常循环系统，这些循环可能与对主要精神疾病的敏感性有关的性别差异可能有关。我们研究的目的是确定遗传和荷尔蒙因素如何相互作用，从而导致大脑的性别分化。该提议集中在上下区域/下丘脑前（POA/ AH）的形成，是研究此过程的关键目标。 POA/AH对于调节稳态，神经内分泌和行为功能很重要。它是激素极大地影响发育以及激素浓缩细胞调节生理和行为的区域。我们假设性腺类固醇激素可以“覆盖”直接的遗传指示，而无激素的发育可以评估基本的遗传指令。具有破坏类固醇生成因子1（SF-1）基因的小鼠永远不会发展性腺，并提供了测试激素依赖性与脑性别分化所选特征独立性的模型。我们的方法使开发过程可访问以实时观察，并在体外进行直接操纵。我们可以将SF-1基因敲除（KO）小鼠成年，以评估无内源性性腺类固醇的脑性别分化的后果。将解决三个主要问题：1）在不同年龄的性腺类固醇调节的胚胎POA/AH中细胞定位的性别差异如何？ 2）一氧化氮产生是否通过影响细胞迁移，细胞死亡或细胞的表型分化的特征来促进POA/AH的发展？ 3）在没有性腺类固醇暴露的情况下，发展的功能后果是什么？这些问题将使用独特的转基因和基因中断模型来解决，这些模型标记了特定的细胞群以进行荧光并防止内源性性腺类固醇激素合成或防止神经产生一氧化氮。拟议的研究将使我们更接近确定与大脑结构和功能中性别差异有关的激素依赖性和独立步骤。