Evolution of gene regulatory networks controlling post-embryonic morphogenesis

控制胚胎后形态发生的基因调控网络的进化 形态发生或形态发育是多细胞发育过程中的普遍过程 由基因调控网络中基因的精确时空表达控制的生物体 (GRNS)。虽然在阐明在模型中控制胚胎发育的GRN方面取得了进展 我们缺乏对GRN如何调控胚胎后形态发生以及这些 网络在不断演变。热点假说预测，GRN的架构可能会对进化产生偏见，从而 形态通过重复选择主调控子(即需要且足够的基因)来进化 形态发生)。这项提议将使用胚胎后形态发生过程，称为尾尖 形态发生(TTM)，在秀丽隐杆线虫及其近缘种中多次独立进化 物种，研究GRN的结构和进化，并检验热点假说。在线虫中， DMD-3是一个DM结构域的转录因子，是GRN调控TTM的主要调节因子。AIM 1使用 在TTM独立进化的谱系中，TTM过程中的时间序列中的单组织RNA-Seq。 然后通过计算推断出每个物种的GRN潜在的TTM。推断的GRN将用于测试 热点假说，将有助于我们对GRN如何驱动形态发生和 GRN架构的可塑性有多高。Aim 2.1通过敲除DMD-3来验证热点假说，或者 另一个候选调控因子从AIM 1中推断，在TTM独立进化的物种中。目标2.2 通过使用单组织RNA-Seq在GRN中验证预测的下游相互作用 调节器拆下管路。目标3研究保守模块的功能作用(即基因和 它们的相互作用)在具有人类同源物的GRN中。由于DMD-3与DMRT-1同源，因此需要 对于人类男性的命运，DMD-3的调节器和效应器可能成为未来药物或 例如，可以帮助人们进行性逆转的疗法。此外，因为形态发生是一种 普遍的发育过程，这项工作也可能识别在其他物种中保守的基因 形态发生过程，如癌症转移、再生和伤口愈合。 这个项目将在纽约大学发育遗传学中心内进行，纽约大学是一个世界- 在大卫·费奇教授的指导下，拥有一流资源和师资的著名研究机构 他在进化论领域有25年的研究、指导和教育经验 发育生物学。我的培训目标是1)扩大我在发育生物学方面的知识，2)学习 发展遗传学湿实验技术，3)继续我的生物信息学教育，4)发展教学 和指导技能，5)将与线虫相关的物种开发成卫星模型系统，用于我的 独立研究生涯。此外，还将以上述研究为平台实现这些目标 从费奇教授的指导、研讨会、会议和指导本科生。

Evolution of gene regulatory networks controlling post-embryonic morphogenesis Morphogenesis, or the development of form, is a universal process during development of multicellular organisms that is controlled by the precise spatiotemporal expression of genes within gene regulatory networks (GRNs). While advances have been made in elucidating GRNs that control embryonic development in model organisms, we lack an understanding of how GRNs regulate post-embryonic morphogenesis and how these networks evolve. The hotspot hypothesis predicts that the architecture of GRNs can bias evolution, such that morphologies evolve via repeated co-option of a master regulator (i.e. a gene that is required and sufficient for morphogenesis). This proposal will use a post-embryonic morphogenic process, known as Tail Tip Morphogenesis (TTM), which evolved multiple times independently in Caenorhabditis elegans and related species, to investigate the architecture and evolution of GRNs, and test the hotspot hypothesis. In C. elegans, DMD-3, a DM-domain transcription factor, is the master regulator within the GRN governing TTM. Aim 1 uses single-tissue RNA-Seq in a time series over the course of TTM in lineages where TTM independently evolved. Then computationally infer the GRN underlying TTM in each species. The inferred GRNs will be used to test the hotspot hypothesis and will contribute to our general understanding of how GRNs drive morphogenesis and how plastic GRN architectures can be. Aim 2.1 validates the hotspot hypothesis by knocking out dmd-3, or another candidate regulator inferred from Aim 1, in species where TTM independently evolved. Aim 2.2 validates the predicted downstream interactions within the GRN by using single-tissue RNA-Seq on the regulator knockout lines. Aim 3 investigates the functional role of conserved modules (i.e. sets of genes and their interactions) within the GRNs that have human homologs. As DMD-3 is a homolog to DMRT-1, required for male fates in humans, regulators and effectors of DMD-3 could be candidate targets for future drugs or therapies that could, for example, help people with sex reversal. Additionally, because morphogenesis is a universal developmental process, this work will also likely identify genes that are conserved in other morphogenic processes, such as cancer metastasis, regeneration, and wound healing. This project will be conducted within the Center for Developmental Genetics at New York University, a world- renowned research institution with top-notch resources and faculty, under the advisement of Prof. David Fitch who has 25 years of experience as a researcher, mentor, and educator in the field of evolutionary developmental biology. My training goals are to 1) expand my knowledge in developmental biology, 2) learn developmental genetics wet lab techniques, 3) continue my education in bioinformatics, 4) develop teaching and mentoring skills, 5) develop species related to C. elegans into satellite model systems to use in my independent research career. These goals will be achieved using the above research as a platform in addition to mentoring from Prof. Fitch, workshops, conferences, and mentoring undergraduates.