09-P069 The clamped s819 gene promotes liver differentiation and growth

The liver forms as part of digestive system. Despite the essential functions of the liver, little is known about its early embryonic development. The clamped s819 mutant was identified in a forward genetic screen for mutations causing defects in endodermal organogenesis in zebrafish. At 44 h post-fertilisation (hpf), clamped s819 mutant embryos display liver hypoplasia and defects in extrahepatic duct morphology. Examination of gene expression indicative of liver specification and differentiation in mutant embryos revealed that specification occurs normally while subsequent differentiation and growth are altered. Similar defects were observed in the developing eyes and fins. Interestingly, in clamped s819 mutants cell death was detected from 40 hpf onwards in the liver abutting mesoderm, and from 48 hpf onwards within the liver and extrahepatic duct. Concomitantly, cell proliferation in the liver of clamped s819 mutants was severely impaired from 44 hpf onwards. Therefore, we hypothesise that Clamped plays a role in promoting hepatic differentiation. Furthermore, Clamped may be required for cross-talk between the mesoderm and endoderm at this stage of liver organogenesis. Mosaic analysis will be carried out to test the tissue autonomous function of Clamped within this process. Positional cloning has mapped the molecular lesion underlying the clamped s819 mutant phenotype to a 240 kb interval on linkage group 14, containing three candidate genes. None of the candidates have so far been implicated in liver organogenesis, thus investigating their function promises to further our understanding of liver differentiation and growth.