Understanding the contributions of cell division and cell death to zebrafish hepatogenesis is the aim of this study. It will be among the first efforts to systematically screen through the zebrafish mutants generated by an insertional mutagenesis screen that is near completion in the Hopkins laboratory. This screen has identified over 500 genes which, when mutated, disrupts early development. A significant portion of these genes have been identified as having a role in either cell division or apoptosis or are novel gene. These mutants will provide fertile ground for both uncovering genes that regulate the balance between cellular life and death during hepatogenesis as well as assigning a function to novel, essential genes.
My first aim i s to provide a detailed description of zebrafish liver development, including delineation of the pattern of cell division and death during hepatogenesis. Second, I will fully characterize the pescadillo (per) mutant which, among other defects, only develops only a rudimentary liver and I will test the hypothesis that hepatogenic failure in pes results from an inability for pes hepatocytes to divide. Third, I will ask whether any of the genes involved in cell division or in apoptosis uncovered by the Hopkins screen contribute to hepatogenesis by investigating the size of the liver and the pattern of liver-specific gene expression during development in these mutants. Finally, I will screen through all of the novel gene mutants to identify those with a defect in liver size. The mutants identified will be subject to further analysis including a description of the mutant, the expression pattern of the gene during wild-type development and a full investigation hepatogenesis so that the function of some of these novel, essential genes may begin to be understood.
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| Sadler, Kirsten C; Amsterdam, Adam; Soroka, Carol et al. (2005) A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease. Development 132:3561-72 |
