Research

Biology and Mechanism of Hedgehog Protein Signaling

The Beachy lab studies how Hedgehog proteins and other extracellular signals function in injury repair and regeneration, primarily through effects on stem cell physiology; we also study abnormal signaling and perturbed stem cell physiology as it occurs in tissue disorders and in the formation and expansion of cancer stem cells. At a more molecular mechanistic level, we study how distribution of the Hedgehog signal in tissues is regulated, how cells perceive and respond to distinct concentrations of signals, and how such signaling pathways arose in evolution.

The biology of Hedgehog signaling

We know that localized expression of the Hedgehog gene and its protein signals provide a spatial coordinate system that directs the formation of the brain, spinal cord, axial skeleton and other organs during embryonic development. Of current interest, we are exploring the roles of these signals in regeneration of a variety of adult tissues, including the urinary bladder, where Hedgehog signaling is part of an epithelial/stromal feedback circuit that controls regenerative proliferation. Building upon this understanding, we are also investigating the influence of stromal niche signals on cancer cancer growth.

The Mechanisms of Hedgehog Signaling

The Hedgehog pathway is unusual in many respects, beginning with the fact that the Hedgehog signal itself is covalently modified by cholesterol and palmitate, thus complicating its release from the membranes of cells that produce it. The response to the Hedgehog signal furthermore is mediated by an unusual receptor system, in which negative control of the pathway is lifted by binding of Hedgehog to the receptor. In addition, many components of the Hedgehog pathway traffic through the primary cilium, which is a staging ground for Hedgehog signal transduction. Our work focuses on all aspects of Hedgehog signal transduction, including:

a) The molecular components and mechanisms involved in packaging and release of the lipid- modified Hedgehog signal as a multivalent particle, which then engages the transporter- like protein Patched and its co-receptors.

b) The mechanism by which Patched negatively regulates the seven-transmembrane protein Smoothened to keep the pathway in check.

c) The molecules and mechanisms by which Hedgehog pathway components traffic through the primary cilium, how the ciliary environment is altered by Hedgehog signaling, and how this change is transmitted by Smoothened to the Gli transcription factors in the cilium and, ultimately, to the nucleus.