Chromatin-based encoding of sex differentiation of neurons

项目摘要 许多物种的动物发育为两种解剖性别，表现出截然不同和复杂的社会行为 行为。在各个分支中，掌握性别决定程序下游的调控转录因子 通过改变神经元数量，“切换”参与典型性行为的不同脑区和神经元， 解剖学和连通性。在昆虫中，雄性特异的转录因子无果(Frum)是在 交配行为的发展，包括对同种雌性处女的先天求爱行为。弗鲁姆 改变组成回路的神经元的数量、解剖结构和连接性。然而，Frum如何 在开发期间执行这些完全不同的基因组程序，当这些程序硬连接时 选择，以及发展格局如何制约FRUM的功能，人们仍然知之甚少。至 为了解决这些问题，我们建议研究Frum是如何建立和维持神经元的变化的 通过改变组成神经元的调控元件的染色质可及性来实现求偶回路。我们 将研究1)Frum对神经发育基因在电路连接和 功能，以及2)确定Frum如何以及何时在染色质环境中作用于硬连接求爱 行为。在这项建议中，我们将由此阐明Fruum硬导线的分子和电路功能 在环路发育过程中的配偶选择和求爱行为。 这份F31建议书描述了针对申请者的全面培训和指导计划，a 密歇根大学细胞和分子生物学专业博士候选人。申请者将会 参加严格的教学和实验室培训课程，由她的赞助人E·乔西博士指导 Clowney和共同赞助商Scott Barolo博士。她将从一个多学科的论文中得到额外的支持 委员会和密歇根大学的扩展神经科学社区。该培训计划包括 广泛而严格的分子遗传学和系统神经科学实验室培训，以及指导 参与科学写作、演讲和拨款申请的机会。这样做的最终目的是 建议是使申请者在独立和多产的科学职业生涯中处于最佳地位。

Project Summary Animals of many species develop as two anatomic sexes that perform distinct and complex social behaviors. Across clades, master regulator transcription factors downstream of sex determination programs “switch” distinct brain regions and neurons involved in sex-typical behaviors by altering neuron number, anatomy, and connectivity. In insects, the male-specific transcription factor Fruitless (FruM) is required during development for mating behaviors, including innate courtship behavior towards conspecific female virgins. FruM changes the number, anatomy and connectivity of neurons which comprise the circuit. However, how FruM executes these disparate genomic programs during development, when these programs hard-wire mate choice, and how the developmental landscape constrains the function of FruM is still poorly understood. To address these questions, we propose to investigate how FruM establishes and maintains changes in neurons of the courtship circuit by altering chromatin accessibility of regulatory elements across constituent neurons. We will investigate 1) the repressive activities of FruM on neurodevelopmental genes in circuit connectivity and function, and 2) determine how and when FruM acts on the chromatin landscape to hard-wire courtship behavior. In this proposal, we will thereby elucidate the molecular and circuit function of FruM that hard-wires mate choice and courtship behavior during development of the circuit. This F31 proposal describes a comprehensive training and mentorship program for the applicant, a Ph.D. candidate in the Cellular and Molecular Biology program at the University of Michigan. The applicant will participate in a rigorous didactic and laboratory training curriculum, supervised by her sponsor, Dr. E. Josie Clowney, and co-sponsor, Dr. Scott Barolo. She will receive additional support from a multi-disciplinary thesis committee and the extended neuroscience community at the University of Michigan. This training plan includes extensive and rigorous molecular genetics and systems neuroscience laboratory training, as well as mentored opportunities to engage in scientific writing, presentations, and grant applications. The ultimate goal of this proposal is to best position the applicant for an independent and productive scientific career.