How cells self-assemble into complex tissues is a fundamental question in biology. The complex tissue system studied here, the Enteric Nervous System (ENS), functions autonomously within the walls of the gut, regulating intestinal movements and homeostatic functions. While it is generally understood how the ENS functions, currently very little is known about the processes ENS progenitor cells use to self-assemble into nervous tissue and form circuits during embryological development. Greater knowledge about how the ENS is generated will facilitate advances in tissue engineering strategies, as well as helping us to better understand how cells get sculpted into specialized tissues. The research addresses two fundamental issues: 1) the cellular behaviors that orchestrate the very first steps in vertebrate ENS formation, and 2) the genetic and molecular mechanisms that underlie these initial steps of ENS construction. Experiments capitalize on the ease of manipulation and optical transparency of zebrafish embryos to quantitatively and mechanistically analyze ENS formation starting from its earliest progenitor cell populations. In addition to supporting graduate student training in quantitative biology and neuroscience, this award will support both the academic-year and summer training of economically-disadvantaged undergraduate students, concomitant with the arrival of the first class of undergraduate students admitted to attend Rice University tuition-free. Additionally, a novel course module will be implemented for students to learn effective scientific communication via the development of critical writing and visual/oral presentation skills; and hands-on zebrafish experimental workshops for local community-college students will be developed and delivered in an outreach capacity.
How and when neural progenitor cells transform into vertebrate enteric nervous system (ENS) neurons has been difficult to study in vivo in mammals, due to the relative inaccessibility of in-utero embryos at the necessary stages of development, and the internal position of the gut within those embryos. The research uses optically-clear, externally-developing zebrafish embryos to overcome these barriers, and identify how enteric neural progenitor cells (ENPs) migrate and embed within their native gut microenvironment. ENP cells can be directly tracking and experimentally manipulated to a degree that is infeasible in other systems. Experiments will quantitatively and functionally analyze ENP cell transformations into ENS using cutting-edge single-cell genomics, high-resolution time-lapse confocal microscopy, computational analyses and quantitative dissection of cellular behaviors over the full course of ENS development. The results from these studies will be used to create mechanistic models to describe the molecular and cellular emergence of ENS from ENPs along the gut microenvironment. Taken together, these results will provide a novel mechanistic framework for understanding how ENS emergence gets orchestrated, and will help transform our scientific understanding of how progenitor cells are sculpted to form specialized cell networks and tissues.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
