The long-term goal of this study is to understand the molecular mechanism by which a Hedgehog (Hh) protein gradient is generated in vertebrates. This information is key to understanding how a single signal elicits multiple responses in a temporally and spatially specific manner in vertebrates. In this regard, a central question in Hh signaling is to understand how a cholesterylated and palmitoylated, and thus membrane-anchored, Hh ligand, travels in the morphogenetic field and generates a protein gradient. This proposal focuses on Sonic hedgehog (Shh), the best characterized mammalian Hh and aims to understand the biogenesis and regulation of a soluble Shh protein complex in Hh-producing cells and how Shh travels in the extracellular space. We propose the following specific aims: 1) Further characterize the soluble Shh protein complex biochemically in order to test the hypothesis that Shh protein complex plays an essential role in Hh signaling. In particular, we aim to identify additional components in the Shh protein complex, including proteins and lipids. 2) Define the role of Dispatched (Disp), a member of the sterol-sensing domain family, in Shh protein complex formation and the requirement of palmitoylation in Disp-mediated Hh protein transport in Hh-producing cells. A cell-based approach utilizing Dz'sp-deficient cells and a genetic approach using knockout mice will be taken to address these issues. 3) Test the hypothesis that heparan sulfate proteoglycans (HSPGs) are dispensable for long-range vertebrate Hh transport and signaling in the extracellular environment but are required for maximal Hh signal transduction in Hh-responsive cells. Similarly, genetic studies utilizing mice deficient in HSPG synthesis and cell-based approaches using cell lines derived from these mice will be taken. These studies will provide new mechanistic insights into how the Hh protein gradient is generated in vertebrates.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Intercellular Interactions (ICI)
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Schramm, Charlene A
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Mak, Kinglun Kingston; Bi, Yanming; Wan, Chao et al. (2008) Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression. Dev Cell 14:674-88
Mak, Kinglun Kingston; Kronenberg, Henry M; Chuang, Pao-Tien et al. (2008) Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135:1947-56
Gerber, A N; Wilson, C W; Li, Y-J et al. (2007) The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation. Oncogene 26:1122-36
Hu, Ming Chang; Mo, Rong; Bhella, Sita et al. (2006) GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development 133:569-78
Mak, Kingston Kinglun; Chen, Miao-Hsueh; Day, Timothy F et al. (2006) Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development 133:3695-707
Wilson, Christopher W; Chuang, Pao-Tien (2006) New ""hogs"" in Hedgehog transport and signal reception. Cell 125:435-8
Chen, Miao-Hsueh; Gao, Nan; Kawakami, Takatoshi et al. (2005) Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 25:7042-53
Chen, Miao-Hsueh; Li, Ya-Jun; Kawakami, Takatoshi et al. (2004) Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18:641-59
Chuang, Pao-Tien; McMahon, Andrew P (2003) Branching morphogenesis of the lung: new molecular insights into an old problem. Trends Cell Biol 13:86-91
Kawahira, Hiroshi; Ma, Nancy H; Tzanakakis, Emmanouhl S et al. (2003) Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development 130:4871-9

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