Abstract

The Hedgehog signaling pathway has critical roles in morphogenic patterning of developing embryos, and functions postembryonically to maintain and repair adult tissues. In its embryonic patterning activities, Hedgehog protein emanating from crucial organizing centers forms signaling gradients that pattern adjacent fields of cells, thus creating an indispensable spatial coordinate system for the developing brain, spinal cord, somites, limbs and other vertebrate organs. In its postembryonic regenerative functions, the Hedgehog protein initiates reciprocal signaling between the epithelium and mesenchyme to coordinate proliferation and differentiation of epithelial stem cells. In this lecture I will discuss my laboratory’s recent findings regarding this regenerative circuitry and its potential manipulation for therapeutic purposes. At the molecular level, I will discuss newly discovered features of Hedgehog signal transduction via its receptor Patched, which acts as a transmembrane cholesterol transporter, and Smoothened, a cholesterol-triggered mediator of pathway activation.