Molecular mechanisms of Hesx1 function in early forebrain development. (360G-Wellcome-084361_Z_07_Z)

Hesx1-deficient mouse embryos show a significant reduction of anterior forebrain (AFB) tissue from 8.5 days post coitum (dpc). Recently, we have demonstrated that the absence of Hesx1 leads to a posterior cell fate transformation of AFB. Our data suggest that HESX1 might function to antagonise the activation of Wnt/?-catenin signalling within the AFB. However, the precise molecular mechanism by which Hesx1 modulates this pathway is not known. Moreover, Hesx1 may perform part of its function inde pendently of this signalling pathway, but there is no information on genes potentially regulated by Hesx1. The main goal of this proposal is to expand our knowledge of the role of Hesx1 during forebrain development by combining two complementary approaches: 1. Hypothesis-driven approach. We will dissect at the molecular level how Hesx1 modulates the Wnt/?-catenin signalling pathway within the AFB. We will perform in vitro studies, on transfected cells, and in vivo experiments, on zebrafish an d mouse models with impaired Wnt/??catenin function. 2. Open-ended screening approach. We will perform gene expression profiling studies on three distinct Hesx1-expressing cells to reveal which molecular pathways other than Wnt/?-catenin are regulated by HESX1. We will identify both common and specific genes, which HESX1 regulates in different cell types.