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: 1456538
• 负责人: Kristi Neufeld
• 金额: $ 50万
• 依托单位: University of Kansas Center for Research Inc
• 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=1456538&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.

了解单细胞合子（受精卵）如何发展成具有多种多样，相互联系和正确指定的组织的多细胞动物，这是我们对包括人类在内的动物如何实际工作的理解的核心。发育生物学中最重要的发现工具之一是秀丽隐杆线虫的小线虫。利用这种生物体的大型国际秀丽隐杆线虫生物学家的国际社会在解释所有动物如何发挥作用的细胞和发育机制方面取得了长足的进步。例如，现在已经知道，相同的细胞通信途径控制了包括秀丽隐杆线虫以及小鼠和人类等哺乳动物在内的各种物种的发展。 该协作项目调查了这些保守途径之一在秀丽隐杆线虫发育中的作用，重点是不对称的干细胞分裂。它将这些研究扩展到干细胞群，肠干细胞的最公认的哺乳动物例子。通过这种方式，它将确定秀丽隐杆线虫干细胞分裂的现有控制模型在哺乳动物中保守的程度。因此，该研究将提供一个强大的框架，以解决这些遥远动物遇到的干细胞的常见问题。该项目将通过面向公众的动手研讨会来扩大这些研究的影响。2）招募下一代STEM科学家，通过将来自爱荷华州农村乡村的大量西班牙裔人口带到校园内的较大的西班牙裔人群的少数招募STEM的科学家，并通过研究当前的STEM范围内的STEM范围内的研究生，并在校园内累积了一段时间，并将其纳入了研究生，并纳入了研究生，并涵盖了跨越的研究，包括扩展的研究，并将其纳入了范围，将其纳入了范围，并纳入了跨越的研究，并纳入了跨越的研究，并纳入了范围的范围。组。非对称细胞分裂（ACD）将动物的细胞命运规格从哺乳动物到线虫。这些生物中的干细胞使用ACD产生分化的女儿和新的干细胞。 Wnt信号传导是通过控制转录激活剂β-catenin的控制ACD和细胞命运的保守调节剂。该项目的目的是通过分析秀丽隐杆线虫β-catenin，sys-1的调节，阐明在非对称干细胞分裂过程中β-catenin调节的机制，并开始测试哺乳动物中所得机制。秀丽隐杆线虫非常适合这些分析，因为其遗传和分子工具，体内ACD成像，β-catenin的信号传导和粘附函数的分离为不同的基因，并且由于最近的发现SYS-1是由beta-catenin Destruction Compliep的同源物负面调节的：Axin，Axin：Axin，APC和CK1alpha。哺乳动物的肠道隐窝，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SYS 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β-catenin在细胞核中的破坏复合物调节的程度。这些研究的结果预计将提供有关发育细胞命运规范的广泛重要见解，以及Wnt途径诱导的ACD在组织稳态中的作用。