CAREER - Building the Vertebrate Body with Axial Stem Cells

和所有其他脊椎动物一样，人类的身体结构是在胚胎形成过程中逐步形成的，头部首先形成，身体的其他部分依次远离头部生长。最近对脊椎动物模型的研究揭示了一个意想不到的发现：一群被称为轴向干细胞的干细胞，通过向分化的脊髓、骨骼肌和血管等提供新细胞，在很长一段时间内为身体的生长过程提供燃料。由于轴向干细胞是最近才被发现的，关于它们在任何物种中的正常发育的信息严重缺乏。本项目旨在建立斑马鱼轴向干细胞诱导、维持和命运规范的分子机制。这项工作将为脊椎动物的身体是如何形成的提供关键的见解，并阐明导致动物王国身体计划多样性的机制。本科生将参与该项目，为他们提供最前沿的研究经验。此外，该项目还将利用斑马鱼作为向高中生教授生物学原理的工具，让他们对发育生物学感到兴奋。这将通过两种机制来实现：1)为高中教师创建专业发展课程，为他们提供在学校运行斑马鱼发展教学实验室所需的培训；2)为高中生提供动手实验模块。这些项目旨在满足不断变化的强调以实验室为基础的动手学习的需求，特别强调向高需求的学区提供这些教育机会。斑马鱼提供了一个无与伦比的系统来研究轴向干细胞生物学。透明胚胎，连同遗传和细胞移植工具，允许精确测定细胞自主，时间作用的途径和基因在体内轴向干细胞内的功能。利用这些方法，本项目研究了轴向干细胞的三个关键方面，包括：1)轴向干细胞在原胚期是如何诱导的，以及在胚胎尾芽形成原胚后是如何维持的；2)典型Wnt信号通路诱导轴向干细胞中胚层的机制；3)Sox2转录因子如何促进轴向干细胞的神经诱导。

The human body plan, along with the body plan of all other vertebrates, is established during embryogenesis in a progressive manner, with the head forming first and the rest of the body growing sequentially away from the head. Recent work in vertebrate animal models revealed the unexpected finding that a population of stem cells, called axial stem cells, fuels the process of body growth over long periods of time by contributing new cells to the differentiating spinal cord, skeletal muscle, and blood vessels, among others. Since axial stem cells have only recently been discovered, there is a severe paucity of information regarding their normal development in any species. The goal of this project is to establish the molecular mechanisms of axial stem cell induction, maintenance, and fate specification in the zebrafish. This work will provide critical insight into how the vertebrate body is created, as well as shed light on the mechanisms leading to body plan diversity across the animal kingdom. Undergraduate students will participate in this project, providing them with a cutting edge research experience. Additionally, the project will also use zebrafish as a tool to teach biological principles to high school students, and to get them excited about developmental biology. This will be accomplished through two mechanisms: 1) the creation of a professional development course for high school teachers that will provide them with the training necessary to run zebrafish development teaching laboratories at their schools, and 2) a hands-on laboratory module for high school students. These programs are designed to meet the needs of the changing emphasis on laboratory-based hands on learning, with a particular emphasis on providing these educational opportunities to high-needs school districts.Zebrafish offer an unparalleled system to investigate axial stem cell biology. The transparent embryos, along with genetic and cell transplantation tools, allow for the precise determination of the cell-autonomous, temporal role of pathways and genes functioning within axial stem cells in vivo. Using these methods, this project investigates three key aspects of axial stem cells, including 1) how axial stem cells are induced during the gastrula stage and maintained after gastrulation in the embryonic tailbud, 2) the mechanism by which the canonical Wnt signaling pathway induces mesoderm within axial stem cells, and 3) how the Sox2 transcription factor promotes neural induction in axial stem cells.