The Hedgehog (Hh) signaling pathway is essential for many aspects of vertebrate embryogenesis and excessive pathway activation can cause cancer in humans. Here I show for the first time that Neuropilins 1 and 2 (Nrp1, 2), a pair of single-pass transmembrane proteins with well-characterized roles in axon chemotaxis and VEGF signaling, are powerful positive regulators of Hh signaling. I identified this new function of Nrp1 in a cell culture RNAi screen and found that Nrp2 is also important for Hh signaling. Both Nrp genes are transcriptional targets of Hh signaling. Increased levels of Nrp1 sensitize cells to Sonic hedgehog (Shh) ligand, indicating the existence of a novel Hh pathway positive feedback circuit. I also demonstrate that Nrps act downstream of Smoothened (Smo) and that their mechanism of action depends upon Suppressor of Fused (SuFu), an essential cytoplasmic regulator of Hh signaling. Furthermore, I explore the mechanism of Nrp action in the Hh pathway as it pertains to the Gli family of transcriptional regulators. Together, these data describe two novel regulators of Hh signal transduction and provide important insight into Hh-mediated morphogenesis and tumor formation.
|Advisor:||Scott, Matthew P.|
|School Location:||United States -- California|
|Source:||DAI-B 71/11, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics|
|Keywords:||Neuropilins, Positive regulators, Signal transduction|
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