Hedgehog signaling is a means of intercellular communication that relies on Smoothened, mutations in which cause cancers such as basal cell carcinoma. We discovered that vertebrate Hedgehog signals move Smoothened to primary cilia, and that this movement is necessary for Smoothened activity. Despite these cell biological insights into Smoothened function, how cilia and Smoothened collaborate to activate the downstream transcriptional effector, Gli2, remains unclear. In this revised renewal application, we examine the molecular mechanisms by which the cilium activates Smo and Gli2. We have discovered that the ciliary membrane is comprised of unique lipids, and that different ciliary lipids are necessary and sufficient to activate mammalian Hedgehog signaling. Therefore, we will test how ciliary lipids participate in Smoothened activation and Hedgehog signaling. How Smoothened communicates to Gli2 remains unknown. We have created a biochemically tractable knock-in Gli2 allele that will allow us to uncover mechanisms of Gli2 activation in embryogenesis and oncogenesis. Additionally, we will assess whether perturbing ciliary lipid composition is a novel means of blocking Hh pathway-related cancer formation. The proposed experiments use a combination of vertebrate genetic, cell biological, imaging and biochemical approaches to reveal how the Hedgehog signal transduction pathway uses cilia to transmit information, both in development and disease.

Public Health Relevance

Primary cilia are small projections found on many human cells involved in receiving and interpreting signals from other cells. Misactivation of Hedgehog signaling, one type of ciliary signaling, cause's cancers, including basal cell carcinoma and medulloblastoma. We are investigating the mechanisms by which Hedgehog ciliary signaling occurs in embryonic development and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054396-09
Application #
9069409
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Baker, Carl
Project Start
2006-12-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Garcia 3rd, Galo; Raleigh, David R; Reiter, Jeremy F (2018) How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In. Curr Biol 28:R421-R434
Siljee, Jacqueline E; Wang, Yi; Bernard, Adelaide A et al. (2018) Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat Genet 50:180-185
Raleigh, David R; Choksi, Pervinder K; Krup, Alexis Leigh et al. (2018) Hedgehog signaling drives medulloblastoma growth via CDK6. J Clin Invest 128:120-124
Reiter, Jeremy F; Leroux, Michel R (2017) Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol 18:533-547
Kopinke, Daniel; Roberson, Elle C; Reiter, Jeremy F (2017) Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis. Cell 170:340-351.e12
Sigg, Monika Abedin; Menchen, Tabea; Lee, Chanjae et al. (2017) Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. Dev Cell 43:744-762.e11
Vaisse, Christian; Reiter, Jeremy F; Berbari, Nicolas F (2017) Cilia and Obesity. Cold Spring Harb Perspect Biol 9:
Shi, Xiaoyu; Garcia 3rd, Galo; Van De Weghe, Julie C et al. (2017) Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome. Nat Cell Biol 19:1178-1188
Garcia-Gonzalo, Francesc R; Reiter, Jeremy F (2017) Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition. Cold Spring Harb Perspect Biol 9:
Phua, Siew Cheng; Chiba, Shuhei; Suzuki, Masako et al. (2017) Dynamic Remodeling of Membrane Composition Drives Cell Cycle through Primary Cilia Excision. Cell 168:264-279.e15

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