Interdisciplinary Initiatives Program Round 5 – 2010

Matthew Scott, Developmental Biology
Jennifer Cochran, Bioengineering

Hedgehog (Hh) signaling is essential for the proliferation and patterning of nearly every cell, tissue, and organ in the developing human embryo. Disruption of Hh signaling at early stages OF development induces spontaneous abortion or gross developmental abnormalities of the fetus, such as the fusion of two orbits into a single cavity containing one eye in the center of the face, a condition known as cyclopia. Despite the importance of Hh signaling in embryonic development, such signaling is largely suppressed in adults. Defects in the cellular machinery responsible for this suppression can lead to several cancers, including the most common human cancer, basal cell carcinoma, and the most common malignant brain tumor in children, medulloblastoma. In contrast, some desirable processes, such as liver generation, require regulated Hh signaling. A comprehensive mechanistic understanding of Hh signaling remains elusive and would greatly benefit the fields of developmental biology, cancer biology, and regenerative medicine. We have discovered that neuropilins (Nrps), single--pass membrane proteins previously implicated in axonal guidance and the formation of new blood vessels from existing ones, are important actors in the Hh signaling pathway. Our efforts seek to elucidate the structural features of Nrps required for Hh signal transduction, which will improve our understanding of this pathway and could provide new therapeutic targets for Hh--‐dependent tumors.