The Hedgehog pathway is one of the fundamental means of controlling mammalian cell behavior and is used to regulate a wide variety of disparate biological events including tissue patterning, stem cell renewal, and cell proliferation. All Hedgehog signaling in organisms ranging from Drosophila to mice relies on the proto-oncogene Smoothened, mutations in which can cause basal cell carcinoma, the most common cancer in North America, and medulloblastoma, the most common solid cancer among children. Despite its importance to both development and disease, the molecular mechanism by which Smoothened functions remains unclear. We have recently discovered that mammalian Hedgehog signals move Smoothened to an organelle called the primary cilium, and that this movement is necessary for Smoothened activity. Although it is known that almost all mammalian cells possess a single primary cilium that extends into the extracellular environment, the functions of this organelle are poorly understood. We propose that the primary cilium acts as a cellular antenna, through which Hedgehog signals are transduced. We seek to build on these findings to investigate how Smoothened acts at the cilium and whether cilia participate in Smoothened-mediated cancer development. Specifically, we will answer four questions: 1) How is the transport of Smoothened to the primary cilium regulated? 2) How does Smoothened activate its pathway at the cilium? 3) Is Smoothened localization misregulated in cancer? 4) Are primary cilia required for Smoothened-mediated oncogenesis? The proposed experiments use genetic, molecular, and biochemical approaches to answer these questions in normal cells, human tumors, and mouse cancer models. This work will both elucidate the mechanism of Smoothened regulation, and assess the function of primary cilia in development and neoplasia. Taken together, these studies will provide a biochemical and cell biological understanding of how Smoothened and the primary cilium regulate Hedgehog signal transduction both in development and in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054396-06
Application #
8289348
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Baker, Carl
Project Start
2007-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$309,385
Indirect Cost
$109,136
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Garcia 3rd, Galo; Reiter, Jeremy F (2016) A primer on the mouse basal body. Cilia 5:17
Li, Chunmei; Jensen, Victor L; Park, Kwangjin et al. (2016) MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. PLoS Biol 14:e1002416
Dinsmore, Colin; Reiter, Jeremy F (2016) Endothelial primary cilia inhibit atherosclerosis. EMBO Rep 17:156-66
Jayaraman, Divya; Kodani, Andrew; Gonzalez, Dilenny M et al. (2016) Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate. Neuron 92:813-828
Roberson, Elle C; Dowdle, William E; Ozanturk, Aysegul et al. (2015) TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J Cell Biol 209:129-42
Garcia-Gonzalo, Francesc R; Phua, Siew Cheng; Roberson, Elle C et al. (2015) Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling. Dev Cell 34:400-9
Yee, Laura E; Garcia-Gonzalo, Francesc R; Bowie, Rachel V et al. (2015) Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling. PLoS Genet 11:e1005627
Vagnozzi, Alicia N; Reiter, Jeremy F; Wong, Sunny Y (2015) Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration. Cell Cycle 14:3408-17
Kodani, Andrew; Yu, Timothy W; Johnson, Jeffrey R et al. (2015) Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. Elife 4:
Santos, Nicole; Reiter, Jeremy F (2014) A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity. J Cell Sci 127:1500-10

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