THE ROLE OF SONIC HEDGEHOG IN VERTEBRATE DEVELOPMENT

Members of the hedgehog family are important signalling molecules duri ng embryonic development. One member, Sonic hedgehog, is expressed in embryonic structures such as the zone of polarizing activity in the po sterior limb bud, the notochord, and the floor plate of the neural tub e, where it plays a role in patterning of the embryo. Sonic hedgehog i s synthesized as an inactive precursor which must be proteolytically c leaved and modified by the addition of a cholesterol moiety to become active as a signalling molecule. In this processing, the C-terminal re gion of Sonic hedgehog serves as both the endoprotease and a cholester ol transferase. The importance of cholesterol for Sonic hedgehog funct ion may explain many of the profound developmental defects caused by p erturbations of cholesterol metabolism. The receptor for Sonic hedgeho g is Patched, a multi-pass transmembrane protein which forms a complex with Smoothened Mutations in Patched are associated with basal cell n aevus syndrome, while mutations in Sonic hedgehog cause holoprosenceph aly. Downstream targets of Sonic hedgehog signalling are transcription factors like Gli3, responsible for Greigs polycephalosyndactyly in hu mans and Hoxd13, responsible for polysyndactyly.