Mechanisms regulating hepatic specification and differentiation in zebrafish

描述（由申请人提供）：

DESCRIPTION (provided by applicant): It has been suggested that the liver and the ventral pancreas originate from common progenitors and share several developmental features. When the liver induction process was prevented in a mouse embryonic tissue explant system by blockig [sic] signals such as Fibroblast growth factors (Fgfs) and Bone morphogenetic proteins (Bmps), the cultured endoderm turned on a gene, Pdx1, that normally expressed in the foregut endoderm [sic], including the stomach, duodenum and pancreas, but not in the liver. Further incubation of these Pdx1 expressing endodermal explants led to the appearance of pancreatic endocrine and exocrine cells, suggesting that the ventral endoderm has the potential to give rise to multiple tissues, including the liver and pancreas. The overall goal of this research proposal is to elucidate mechanisms regulating liver specification and its plasticity, and subsequent differentiation using zebrafish as the main model organism. First, I will investigate how Bmp2b regulates liver versus pancreatic fate decision by performing more detailed lineage tracing analysis ad [sic] loss- and gain-of-function epistatic analysis of Wnt2bb and Bmp2b signaling as well as Hedgehog and Bmp2b signaling. Second, I will investigate how Forkhead box and Homeobox transcription factors function downstream of Bmp2b signaling to regulate liver versus pancreatic fate decision. Expression analysis as well as endoderm-specific loss-and gain-of-function experiments will be performed. Third, I will perform detailed characterization of 4 mutants from large scale mutagenesis screening. They show specific defects in the growth and differentiation of endodermal organs. Once prioritized, identification of the underlying molecular lesion will be followed by extensive analysis, such as expression pattern analysis and loss-and gain-of-function studies. I expect I can answer the fundamental question how the liver and pancreas develop from common progenitors to acquire their unique and overlapping function with series of these experiments. PUBLIC HEALTH RELEVANCE: Liver disease is a major cause of death in the United States and world wide. In general it reflects a chronic response to injury, in which repair and regeneration lead to scarring and/or neoplasia. Often, repair and regeneration in the adult recapitulate embryonic development. Thus, understanding the mechanisms of development has direct implications for prevention and treatment of chronic injury and liver cancer.