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.
