Abstract
The Hedgehog (Hh) pathway is a critical signaling pathway in vertebrate embryogenesis. Hillman et al. now identify neuropilin (Nrp) proteins as novel players in Hh signaling. Nrps were known to have roles in axon guidance and VEGF signaling. The authors identify the Nrps as part of a new Hh positive feedback circuit, controlling Hh transduction downstream from Smoothened activation and regulating the pathway between Smoothened and the negative regulator SuFu. This role for Nrps is further found to be conserved between mammals and zebrafish.
The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator Suppressor of Fused (SuFu).
Nrp1
transcription is induced by Hh signaling, and
Nrp1
overexpression increases maximal Hh target gene activation, indicating the existence of a positive feedback circuit. The regulation of Hh signal transduction by Nrps is conserved between mammals and bony fish, as we show that morpholinos targeting the Nrp zebrafish ortholog
nrp1a
produce a specific and highly penetrant Hh pathway loss-of-function phenotype. These findings enhance our knowledge of Hh pathway regulation and provide evidence for a conserved nexus between Nrps and this important developmental signaling system.