Regulation of pancreatic islet location and size during embryonic development

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DESCRIPTION (provided by applicant): This project is focused on vertebrate pancreas development. I have previously shown that Cdx4 transcription factor is required to limit beta-cell number during development. I have also shown that Cdx4 is required in the endoderm to correctly localize the pancreas. Here I propose to extend that work by further characterizing the role of Cdx4 in pancreas development. I will use zebrafish as an vivo model. Aim 1 will determine the mechanism whereby beta-cell number is limited during early pancreas organogenesis. I will use Cdx4 mutant embryos to test whether beta-cells, or their precursors, have increased proliferation in the absence of Cdx4. This aim will determine the mechanism whereby islet size is limited during normal pancreas development. Aim 2 will test the hypothesis that Wnt signals function upstream of Cdx4 to localize the pancreas. Aim 3 will test the hypothesis that endodermal Hox factors function downstream of Cdx4 to pattern the pre-pancreatic endoderm. Thus, Aims 2 & 3 will identify and characterize factors that function upstream and downstream of Cdx4 during anteroposterior patterning of the pancreatic domain. These aims were designed with the career goal of developing my current research into a more mature research program that will allow me to secure R01 funding in the future, as an independent PI. My immediate goals are to learn new techniques relevant to completing and publishing these aims. My long-term career goals include a commitment to studying pancreas development and function using zebrafish as a model. I plan to secure a tenure-track, full-time Assistant Professor position at an academic institution, where research would be my primary focus. The career development plan includes training via a mentoring committee composed of two developmental biologists, Victoria Prince, PhD and Robert Ho, PhD, both of whom study zebrafish development, and a diabetes physician scientist. Louis Philipson, MD, PhD, who studies mouse and human pancreas biology and diabetes. I will meet regularly with the committee for evaluation of my research and career development progress. PUBLIC HEALTH RELEVANCE: These aims have relevance for stem-cell based diabetes research. Current protocols for directing stem-cells to a beta-cell fate have benefited from insights learned from in vivo developmental studies. The proposed work will extend our current knowledge of how undifferentiated endoderm is patterned to become pancreas, and how beta-cell number is modulated by the embryo.