Reconstructing the ancestral neural crest-pluripotency gene regulatory network - Project Summary Understanding how stem cell attributes are controlled and how they evolve to generate diverse and novel cell types is essential to understanding how mis-regulation of these processes results in stem cell-linked pathologies. My research will focus on two key stem cell populations, pluripotent blastula stem cells and neural crest (NC) stem cells that both arose at the base of the vertebrates. NC cells give rise to many of the hallmark anatomical, physiological and behavioral traits of vertebrate animals—including humans—and defects in the development of these cells is linked to a broad set of birth defects and cancers. Previous work has shown that the gene regulatory networks (GRNs) deployed in NC cells and blastula stem cells are highly overlapping. The overall goal of this project is to use comparative studies in three organisms that represent key nodes in the chordate phylogeny to dissect the gene regulatory logic underlying the development and evolution of these important stem cell populations in vertebrates. Under the mentorship of my sponsoring scientist and career advisory board I will combine genomic and functional studies in a jawed vertebrate (Xenopus laevis), a basal jawless vertebrate, the sea lamprey (Petromyzon marinus), and an invertebrate chordate (Ciona intestinalis). My research will trace the developmental origins of “stemness” in vertebrates and provide novel insights into the molecular-genetic processes controlling how stem cells arise in the embryo and how aberrant execution of these processes leads to defects in the formation of these key stem cells that are essential for early embryonic development. My mentored training plan during the K99 phase of my research as a postdoctoral fellow will enable me to incorporate a new model system, Ciona, into my research program, develop new experimental techniques, and acquire expertise in cutting-edge, single-cell “multiomic” approaches and associated bioinformatic and computational analyses. During the R00 phase I will utilize this new expertise to provide novel insights into the molecular, cellular, and developmental mechanisms underlying the formation and maintenance of these stem cell populations at unprecedented single-cell resolution. My sponsor and advisory board members are outstanding scientists and mentors whose expertise will catalyze my transition to Principal Investigator of my own laboratory. My long-term career goal is to establish a productive independent research program that uses multiple model systems to make important discoveries about the gene regulatory control of stem cell attributes during development and evolution, and how mis-regulation of these processes leads to congenital defects and cancers.
