Collaborative Research: Beta-catenin Regulation during Asymmetric Stem Cell Divisions

合作研究：不对称干细胞分裂过程中β-连环蛋白的调节

• 批准号: 1456941
• 负责人: Bryan Phillips
• 金额: $ 70万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1456941&HistoricalAwards=false
• 关键词: Collaborative; Research; Beta; catenin; Regulation

Understanding how a single-celled zygote (the fertilized egg) develops into a multicellular animal with diverse, interconnected and properly-specified tissues is core to our understanding of how animals, including humans, actually work. One of the great discovery tools in developmental biology is the small nematode, Caenorhabditis elegans. Taking advantage of the available genetic tools in this organism, the large international community of C. elegans biologists, has made great strides in explaining the cellular and developmental mechanisms that govern how all animals function. For instance, it is now known that the same cell communication pathways control the development of diverse species, including C. elegans, and mammals like mice and humans. This collaborative project investigates the role of one of these conserved pathways in C. elegans development, focusing on asymmetric stem cell divisions. It will extend these studies to the most well-established mammalian example of a stem cell population, intestinal stem cells. In this way, it will determine the extent to which existing models of control of C. elegans stem cell divisions are conserved in mammals. Thus the research will provide a strong framework to address common problems that stem cells in these distantly-related animals encounter. The project will broaden the impact of these studies by 1) increasing public engagement and science literacy through hands-on workshops geared toward the general public, 2) recruiting the next generation of STEM scientists by bringing 8th graders from rural Iowa communities with large Hispanic populations to campus for a day of career simulations and 3) retaining current STEM undergraduates by extending undergraduate research opportunities, including to disadvantaged and underrepresented groups. Asymmetric cell division (ACD) drives cell fate specification in animals from mammals to nematodes. Stem cells in these organisms use ACD to generate a differentiated daughter and a new stem cell. Wnt signaling is a conserved regulator of ACD and cell fate through its control of the transcriptional activator beta-catenin. The goal of this project is to elucidate the mechanisms of beta-catenin regulation during asymmetric stem cell divisions by analyzing regulation of the C. elegans beta-catenin, SYS-1, and to begin testing the resulting mechanisms in mammals. C. elegans is well-suited for these analyses because of its genetic and molecular tools, in vivo ACD imaging, the separation of the signaling and adhesion functions of beta-catenin into distinct genes and because of recent findings that SYS-1 is negatively regulated by homologs of the beta-catenin destruction complex: Axin, APC and CK1alpha. The mammalian intestinal crypt, arguably the best-known example of Wnt-controlled stem cell maintenance, will be used to test conservation of SYS 1 regulatory mechanisms and will also inform the worm models. This project will determine the mechanism by which Axin localizes the destruction complex, and the extent to which destruction complex regulation of beta-catenin in the nucleus is conserved. The results of these studies are predicted to provide broadly important insight into developmental cell fate specification and the role of Wnt pathway-induced ACD in tissue homeostasis.

了解一个单细胞受精卵（受精卵）如何发育成一个多细胞动物，具有不同的，相互连接的和适当指定的组织是我们理解动物（包括人类）如何工作的核心。发育生物学中最重要的发现工具之一是小型线虫，秀丽隐杆线虫。利用现有的遗传工具，在这种有机体，大的国际社会的C。在解释支配所有动物功能的细胞和发育机制方面取得了很大进展。例如，现在已经知道，相同的细胞通讯途径控制着不同物种的发育，包括C。以及像老鼠和人类这样的哺乳动物 这个合作项目调查的作用，这些保守的途径之一，在C。elegans发育，专注于不对称干细胞分裂。它将把这些研究扩展到最成熟的哺乳动物干细胞群，肠道干细胞。通过这种方式，它将决定在何种程度上，现有的控制模式的C。线虫干细胞分裂在哺乳动物中是保守的。因此，这项研究将提供一个强有力的框架来解决这些远亲动物中干细胞遇到的常见问题。该项目将通过以下方式扩大这些研究的影响：1）通过面向公众的实践研讨会增加公众参与和科学素养，2）通过将来自拥有大量西班牙裔人口的爱荷华州农村社区的8年级学生带到校园进行为期一天的职业模拟来招募下一代STEM科学家，3）通过延长本科生研究机会来留住当前的STEM本科生，包括弱势群体和代表性不足的群体。不对称细胞分裂（ACD）驱动从哺乳动物到线虫动物的细胞命运特化。这些生物体中的干细胞使用ACD产生分化的子细胞和新的干细胞。Wnt信号是ACD和细胞命运的保守调节因子，通过其对转录激活因子β-连环蛋白的控制。本项目的目的是通过分析C. elegans beta-catenin，β-catenin-1，并开始在哺乳动物中测试由此产生的机制。C.由于其遗传和分子工具、体内ACD成像、将β-连环蛋白的信号传导和粘附功能分离到不同的基因中，以及由于最近发现β-连环蛋白破坏复合物的同源物Axin、APC和CK 1 α负调控，elegans非常适合这些分析。哺乳动物的肠隐窝，可以说是Wnt控制的干细胞维持的最著名的例子，将用于测试Wnt 1调节机制的保护，也将为蠕虫模型提供信息。该项目将确定Axin定位破坏复合物的机制，以及细胞核中β-连环蛋白的破坏复合物调节的保守程度。这些研究的结果预测提供了广泛的重要洞察发育细胞的命运规范和Wnt途径诱导的ACD在组织内稳态的作用。