REGULATION OF THE HEDGEHOG SIGNALING PATHWAY IN NEURAL DEVELOPMENT AND STEM CELLS

Holoprosencephaly is a genetic disease characterized by incomplete cleavage of the brain during embryogenesis and is caused by genetic defects in members of the Hedgehog pathway, which are also responsible for a number of additional inherited diseases characterized by aberrant development of the nervous and other tissues (Grieg Cephalopolysyndactyly, Pallister-Hall syndrome, Postaxial Polydactyly and VACTERIL), including brain tumors (Gorlin syndrome). However, there remain many gaps in understanding Hedgehog functions and its association with diseases. Filling this gaps appears critically important for the elucidation of pathogenetic issues and for the identification of potential therapeutic targets. We have recently identified a novel gene (REN) that controls neural cell development and is a new regulator of the Hedgehog functions. We have also identified a novel mechanism of regulation of the Hedgehog pathway, involving the developmental protein Numb that plays a critical role in neural stem cell fate determination. This proposal plans to study whether these novel regulators may play a role in diseases caused by genetic defects of Hedgehog pathway and may represent targets for stem cell-based novel therapeutic strategies.