Sexual Dimorphism Among Glia in the Nervous System

神经系统神经胶质细胞的性别二态性

• 批准号: 10663354
• 负责人: Wendy Fung
• 金额: $ 1.96万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663354
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Automobile Driving; Behavior; Behavioral Assay; Biological; Biological Assay; Caenorhabditis elegans; Cell secretion; Cells; Cilia; Data; Development; Environment; Excision; Exhibits; Extracellular Matrix; Female; Feminization; Gene Expression; Genes; Genetic Screening; Genetic Transcription; Goals; Head; Human; Label; Lead; Mediating; Modeling; Molecular; Nervous System; Nervous System Physiology; Neurobiology; Neuroglia; Neurons; Partner in relationship; Pathway interactions; Phenotype; Pheromone; Prevalence; Protein Secretion; Reporter; Schizophrenia; Sensory; Sex Bias; Sex Differences; Sexual Development; Stereotyping; Study models; System; Testing; Time Factors; Visualization; Work; autism spectrum disorder; cell type; disorder risk; genetic approach; genetic manipulation; innovation; male; mating behavior; mutant; nervous system disorder; neural circuit; neuronal survival; neurotransmission; novel; novel marker; protein kinase D; response; sex; sexual dimorphism; sexual identity; single cell sequencing; single-cell RNA sequencing

PROJECT SUMMARY/ABSTRACT The nervous system is sexually dimorphic: sex-specific behaviors are observed across species and disease risk for many neurological disorders, including autism and Alzheimer’s disease, differs between males and females. How sex-specific functions of the nervous system are established remains a fundamental question in neurobiology. Glia are ideal candidates for driving these sex-specific functions. They promote the formation and removal of neuronal connections, modulate neuronal activity, and most notably, exhibit sex differences in gene expression. However, due to technical challenges in studying glia in mammalian systems, it remains unclear how glial sex differences arise and how they affect neuronal function. I will overcome these challenges by using an innovative model of sexually dimorphic glia in the highly tractable nervous system of C. elegans. Specifically, I will investigate sex differences in a glial subtype called CEPso glia. We discovered that a transcriptional reporter for a putative secreted protein (GRL-18) is expressed exclusively in CEPso glia of sexually mature males. We determined that male-specific gene expression in CEPso glia is controlled cell-autonomously and requires conserved regulators of sexual development, including the timing genes lep-2/Makorin and lep-5 and the sex identity gene mab-3/DMRT. Interestingly, CEPso glia are intimately associated with male-specific CEM neurons that begin responding to pheromones in the external environment and mediating male mate-seeking behavior at sexual maturity. This leads to our hypothesis that sex differences in glia promote the activation of a sex-specific circuit at sexual maturity. In Aim 1, I will determine the molecular mechanisms that establish glial sex differences. First, I will use single-cell sequencing approaches to comprehensively identify sexually dimorphic gene expression in CEPso glia and other glia of the adult nervous system. Next, I will use classical genetic approaches and unbiased genetic screens to identify novel regulatory factors that act downstream of conserved timing and sex identity factors to initiate sex-specific changes in glia. The significance is to identify glial-specific regulators that control sexually dimorphic gene expression. In Aim 2, I will determine whether sex-specific glial gene expression contributes to sex-specific neuronal functions and behavior. To test this, I will assay aspects of CEM neuron maturation and adult male mate-seeking behavior in wild type and mutant animals with feminized glia or lacking male-specific genes, including grl-18. The significance will be to show how glia switch on sex-specific circuits and behaviors in the adult nervous system, which can help to explain the striking sex biases observed in many neurological disorders.

项目总结/摘要 神经系统是性二态的：性别特异性行为在物种和疾病中都可以观察到。 许多神经系统疾病的风险，包括自闭症和阿尔茨海默病，在男性和女性之间是不同的。 女性神经系统的性别特异性功能是如何建立的，这仍然是一个基本问题， 神经生物学胶质细胞是驱动这些性别特异性功能的理想候选者。它们促进了 去除神经元连接，调节神经元活动，最值得注意的是，在基因表达上表现出性别差异。 表情然而，由于在哺乳动物系统中研究神经胶质细胞的技术挑战， 神经胶质细胞的性别差异是如何产生的，以及它们是如何影响神经元功能的。 我将通过使用一种创新的性二态胶质细胞模型来克服这些挑战， C.易处理的神经系统。优雅的具体地说，我将研究一种叫做 CEPso glia.我们发现，一个假定的分泌蛋白（GRL-18）的转录报告基因表达， 仅在性成熟雄性的CEPso神经胶质中。我们确定CEPso中的男性特异性基因表达 神经胶质是细胞自主控制的，需要保守的性发育调节因子，包括 时间基因lep-2/Makorin和lep-5以及性别鉴定基因mab-3/DMRT。有趣的是，CEPso胶质细胞 与男性特定的CEM神经元密切相关，CEM神经元开始对外部环境中的信息素做出反应。 环境和调解男性求偶行为在性成熟。这就引出了我们的假设， 胶质细胞的性别差异促进性成熟时性别特异性回路的激活。 在目标1中，我将确定建立胶质细胞性别差异的分子机制。首先，我将使用 用单细胞测序方法全面鉴定CEPso中的性二态基因表达 神经胶质细胞和其他神经胶质细胞。接下来，我将使用经典的遗传方法和无偏遗传方法， 筛选以鉴定在保守的时间和性别鉴定因子下游起作用的新的调节因子， 引发胶质细胞性别特异性变化。其意义在于确定控制性行为的神经胶质特异性调节因子， 双态基因表达在目标2中，我将确定性别特异性胶质基因表达是否有助于 性别特异性神经元功能和行为。为了验证这一点，我将分析CEM神经元成熟的各个方面， 在野生型和具有雌性化胶质细胞或缺乏雄性特异性的突变动物中的成年雄性求偶行为 基因，包括GRL-18。其意义在于揭示胶质细胞如何在性别特异性电路和行为上进行切换 这可以帮助解释在许多神经系统中观察到的惊人的性别偏见。 紊乱