Noël, E.S.; (2009) Early liver formation in zebrafish: a molecular and morphological approach. Doctoral thesis , UCL (University College London).

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Abstract

The digestive tract and its accessory organs - liver, pancreas, and the inner lining of the swim bladder - are derived from the endodermal germ layer. In zebrafish the digestive system starts out as a rod at the embryonic midline, which subsequently becomes patterned and outgrowth of its associated organs occurs. Liver formation can be subdivided into three distinct phases; specification, budding, and differentiation and growth. Despite the importance of the liver for body homeostasis, relatively little is known about the mechanisms of liver development. The transgenic line Tg(gutGFP)s854, expressing GFP throughout the developing digestive tract, was used to identify the mutant lines s436 and 4C1 in a forward genetic screen for mutants displaying defects in endodermal organogenesis. Initial analysis of both lines revealed a hypoplastic liver at 48 hpf, and in addition distinct defects in pancreas formation. Positional cloning of the s436 line identified a novel allele of histone deacetylase 1 (hdac1), which plays distinct roles in endodermal organogenesis in zebrafish. Loss of Hdac1 causes defects in timely liver specification and subsequent differentiation, while mosaic analyses revealed a cell-autonomous role for Hdac1 in the endoderm in these processes. In addition, I have demonstrated that Hdac1 has specific functions in endocrine pancreas morphogenesis, as well as roles in exocrine pancreas specification and differentiation. Finally, loss of Hdac1 results in an expansion of the foregut endoderm in the domain from which the liver and pancreas originate, suggesting a scenario whereby Hdac1 may directly or indirectly restrict foregut fates while promoting hepatic and exocrine pancreatic specification and differentiation. Phenotypic characterisation of endodermal organogenesis in 4C1 mutant embryos revealed a requirement for 4C1 in specification of the correct number of hepatic progenitors and hepatic bud morphogenesis. This is accompanied by a subsequent requirement for 4C1 in hepatic growth and duct morphogenesis. Additionally, 4C1 mutants exhibit defects in exocrine pancreas anlage outgrowth, leading to ectopic exocrine bud formation, suggesting a role for 4C1 in the morphogenesis of this organ. Preliminary analysis suggests that 4C1 may be required within the neighbouring tissue, the lateral plate mesoderm, to promote endodermal organogenesis. Taken together, I have characterised two novel mutant lines, which despite initial phenotypic similarities, exhibit very distinct defects in liver as well as pancreas formation, highlighting important roles for these genes in the processes underlying endodermal organogenesis.

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