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 #
5R01AR054396-07
Application #
8500569
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Baker, Carl
Project Start
2007-07-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$293,915
Indirect Cost
$103,679
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Kodani, Andrew; Salome Sirerol-Piquer, Maria; Seol, Allen et al. (2013) Kif3a interacts with Dynactin subunit p150 Glued to organize centriole subdistal appendages. EMBO J 32:597-607
D'Amico, Eva; Gayral, Stephanie; Massart, Claude et al. (2013) Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism. J Mol Endocrinol 50:375-87
Saqui-Salces, Milena; Dowdle, William E; Reiter, Jeremy F et al. (2012) A high-fat diet regulates gastrin and acid secretion through primary cilia. FASEB J 26:3127-39
Hunkapiller, Julie; Shen, Yin; Diaz, Aaron et al. (2012) Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal. PLoS Genet 8:e1002576
Croyle, Mandy J; Lehman, Jonathan M; O'Connor, Amber K et al. (2011) Role of epidermal primary cilia in the homeostasis of skin and hair follicles. Development 138:1675-85
Wong, Sunny Y; Reiter, Jeremy F (2011) Wounding mobilizes hair follicle stem cells to form tumors. Proc Natl Acad Sci U S A 108:4093-8
Hunkapiller, Julie; Singla, Veena; Seol, Allen et al. (2011) The ciliogenic protein Oral-Facial-Digital 1 regulates the neuronal differentiation of embryonic stem cells. Stem Cells Dev 20:831-41
Dowdle, William E; Robinson, Jon F; Kneist, Andreas et al. (2011) Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet 89:94-110

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