Welcome to the University of Colorado School of Medicine on the Anschutz Medical Campus. We are a Top Ten Medical School in primary care, pediatrics, family medicine and rural medicine, and offer physical therapy and physician assistant programs.

We are interested in the cellular and molecular mechanisms that underlie pattern formation in embryos and tissue maintenance in adults. The short-range cell interactions that mediate these processes often involve the evolutionarily conserved Hedgehog (Hh) signaling pathway (Hooper and Scott, 2005). Dysfunction of the Hh pathway during fetal development leads to many common birth defects, while its inappropriate activation later in life can cause cancer. We are integrating genetic, molecular genetic, and biochemical approaches to understand regulation within the Hh signal transduction pathway; how Hh generates dose dependent responses and how multiple signals are integrated to select different cell fates, to direct growth, and/or to drive apoptosis.

We have identified two cell surface transmembrane proteins, Patched and Smoothened, which cooperate to regulate intracellular responses to Hh (Hooper and Scott 1989, Alcedo et. al. 1996, Stone et. al. 1996). Smoothened is an integral membrane protein belonging to the serpentine receptor family while Patched is a pioneer protein with 12 transmembrane segments. Smoothened activates intracellular Hedgehog responses, Patched inhibits those responses, and is in turn, regulated by binding Hedgehog.

We have shown that the zinc-finger protein encoded by the cubitus interruptus gene (ci) is the transcriptional effector of Hh signaling (Von Ohlen et. al. 1997, Von Ohlen and Hooper 1997). Ci is post-translationally regulated by Hh; modest levels of Hh prevent Ci from becoming a transcriptional repressor, while high levels of Hh allow Ci to become a transcriptional activator. The choice is mediated by a regulatory complex that includes Costal (kinesin-like), Fused (S/T kinase), and Sufu. We have recently shown that Smoothened controls activity of the regulatory complex via direct interaction with Costal (Ogden et al., 2003). Moreover, two distinct activities of Smoothened control production of Ci-repressor and Ci-activator (Hooper, 2003). Current work is focusing on which aspects of Smoothened contribute to each of these activities.

We have identified roadkill as a gene involved in feedback inhibition of Hedgehog signaling. roadkill, a transcriptional target for Ci, encodes a protein which acts as part of an E3 ubiquitin ligase to degrade Ci (Kent, submitted). We are currently asking whether the human homologue for Roadkill plays a similar role in regulating the human homologues of Ci. These studies should provide a molecular mechanism for how different levels of Hedgehog acts through Smoothened to activate distinct responses. In the longer term they will identify potential targets for therapeutic intervention in Hedgehog-related pathologies.