NSF Postdoctoral Fellowship in Biology FY 2021: Defining the role of ZEB2 in the development of convergent neural circuitry for vocal imitation

该行动资助2021财年NSF生物学博士后研究奖学金，研究基因组，环境和表型之间相互作用的生命规则的综合研究。该奖学金支持将以创新方式为《生活规则》领域作出贡献的研究员的研究和培训。鸣禽、鹦鹉和人类的声音模仿被认为是趋同进化的，因为尽管这三个群体没有共同的祖先，但它们在学习唱歌和说话方面表现出相似的大脑通路。塑造这些共同的大脑通路和行为的基因驱动因素尚不清楚。最近的跨物种比较暗示ZEB2是形成这些脑通路的重要基因，包括ZEB2突变导致人类语言产生受损。本项目旨在了解ZEB2在鸣禽和鹦鹉的声音模仿脑通路的发育和功能中的作用，并将这些发现与人类联系起来。更广泛的影响包括通过生物信息学研讨会加强代表性不足的少数民族学生对STEM的参与。为了测试ZEB2在鸣禽和鹦鹉趋同声音模仿神经回路形成中的必要性，该项目旨在1)评估特定大脑区域表达操纵后的行为结果，2)定义两种物种中与表达操纵相关的转录组和染色质修饰。该研究员将使用rnai介导的病毒表达载体来敲除鸣禽HVC（高发声中枢）和鹦鹉NLC（侧毛中央核）中的ZEB2，这两个重要的运动前类似物被证明可以控制鸟类习得发声的时间。在形成专门的声音模仿连接之前，将在发育早期引入这种操作，以测试ZEB2在这一过程中的作用。转录组学分析将被执行，以确定下游靶基因在两个物种的影响。该研究员还将利用ChIP-Seq分析这两个物种中这些大脑区域和邻近非声音模仿区域的染色质可及性，分析ZEB2转录因子的调控前景，突出声音模仿的重要分子途径。总而言之，该项目将为跨类群复杂行为趋同进化的基因组约束提供重要见解，同时为未来的研究提供数十个新的候选基因。该研究员将发展神经科学、体内基因操作和基因组测序方面的专业知识，并将通过新密歇根州立大学的RISE项目教授基于r的生物信息学研讨会。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2021, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment and Phenotypes. The fellowship supports research and training of the Fellow that will contribute to the area of Rules of Life in innovative ways. Vocal imitation is thought to have evolved convergently in songbirds, parrots, and humans because, despite not sharing a common ancestor with this trait, these three groups exhibit similar brain pathways for the production of learned song and speech. The genetic drivers that shape these shared brain pathways and behaviors are not known. Recent cross-species comparisons implicate ZEB2 as a gene important for forming these brain pathways, including that ZEB2 mutations result in impaired speech production in humans. This project aims to understand the role of ZEB2 in the development and function of vocal imitation brain pathways in songbirds and parrots and to relate these findings to humans. Broader impacts include enhancing participation of underrepresented minority students in STEM through a workshop on bioinformatics. In order to test the necessity of ZEB2 for the formation of convergent vocal imitation neural circuitry in songbirds and parrots, the project aims to 1) assess behavioral outcomes following expression manipulation in specific brain regions and 2) define the transcriptomic and chromatin modifications associated with expression manipulation in both species. The Fellow will use RNAi-mediated viral expression vectors to knockdown ZEB2 in songbird HVC (high vocal center) and parrot NLC (central nucleus of the lateral nidopallium), two important premotor analogs shown to control the timing of learned vocalizations in birds. This manipulation will be introduced early in development prior to the formation of the specialized vocal imitation connectivity to test ZEB2’s role in this process. Transcriptomic profiling will be performed to determine the downstream target genes impacted in both species. The Fellow will also profile the regulatory landscape of the ZEB2 transcription factor in both species using ChIP-Seq analysis for chromatin accessibility in these brain regions and adjacent non-vocal imitation regions, highlighting important molecular pathways for vocal imitation. In sum, this project will offer important insights into the constraints on the genome for the convergent evolution of complex behaviors across taxa while offering dozens of new candidate genes for future study. The Fellow will develop expertise in neuroscience, in vivo gene manipulation, and genomic sequencing and will teach a R-based bioinformatics workshop through the RISE program at NMSU.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.