Hedgehog signaling is a conserved cell-cell communication pathway that plays essential and diverse roles during embryonic development and adult tissue homeostasis. Many cell surface-associated molecules critically regulate the Hedgehog signaling pathway, coordinating the secretion and distribution of Hedgehog ligands as well as signal reception and downstream signal transduction. Recent evidence suggests that Neuropilins, single-pass transmembrane receptors for Semaphorin and vascular endothelial growth factor ligands, positively regulate Hedgehog signaling. However, the mechanism of Neuropilin action in Hedgehog signal transduction remains unclear. Neuropilins require Plexin co-receptors to transduce Semaphorin signals, although a role for Plexins in HH signaling has not been explored. These questions are particularly interesting given overlapping expression of HH and Semaphorin components in both development and disease. Investigating how Semaphorin receptors function within the Hedgehog signaling cascade will provide important insight into the regulation of this key developmental pathway. Furthermore, therapeutic approaches targeting Semaphorin receptors may be useful to regulate deregulated Hedgehog signaling in cancer and other diseases. In this chapter, I review both the Hedgehog and Semaphorin signal transduction pathways, emphasizing areas of overlap between these two pathways which could be mediated by Neuropilin and Plexin receptors.
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Semaphorin Receptor Function in Hedgehog Signal Transduction
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