02-P004 A zebrafish model to characterize von Hippel-Lindau disease

Little is known about the respective contributions of cell proliferation and cell death to the control of vertebrate forebrain growth. The homeodomain containing gene barhl2 is expressed in the diencephalon of Xenopus, zebrafish, and mouse embryos, and we previously showed that its over-expression in Xenopus neuroepithelial cells induces Caspase3-dependent apoptosis. These findings suggested that Barhl2 and Caspase3 might be involved in diencephalic growth and morphogenesis. Consistent with this suggestion, we have demonstrated that depletion of either protein causes an increase in diencephalic cell proliferation, disturbance in interkinetic nuclear migration and altered differentiation of the prosomere P2 alar plate. Surprisingly, however, these changes are not caused by decreased apoptosis but instead are caused by an increase in the level and activation of b-catenin, which stimulates excessive neuroepithelial cell proliferation. Thus Caspase3 and Barhl2 normally inhibit neuroepithelial cell proliferation in the developing diencephalon by inhibiting b-catenin activation and our data reveal critical cross-talk between Caspase3 and b-catenin—two major regulators of cell proliferation and apoptosis, respectively.