Hedgehog signaling is a means of intercellular communication that, in vertebrates, relies on immotile cellular appendages called primary cilia. In our previous work, we discovered that vertebrate Hedgehog signals move Smoothened to primary cilia, that this movement is necessary for Smoothened activity, and that certain cancers depend on their cilia for constitutively active Hedgehog pathway activity. Despite these insights into Hedgehog signaling, how Smoothened movement to cilia is regulated and how ciliary Smoothened activates the downstream pathway remain unclear. In this renewal application, we examine the molecular mechanisms by which the Hedgehog receptor, Patched1, controls Smoothened activity (Aim 1), how Smoothened is activated within the cilium (Aim 2), and how Smoothened activates its downstream effector, the transcription factor GLI2 (Aim 3). We have discovered that the ciliary membrane has a unique lipid composition, and that specific ciliary lipids are necessary and sufficient to activate mammalian Hedgehog signaling. Therefore, the first two aims focus, in part, on how Patched1 regulates ciliary lipids and how ciliary lipids control Smoothened activity. These experiments will help reveal how lipids control signaling, and may identify new therapeutic strategies for blocking Hedgehog pathway-related cancer formation. How Smoothened communicates to GLI2 remains unknown. We have created a biochemically tractable knock-in Gli2 allele that will allow us to uncover mechanisms by which cilia regulate GLI2 activity in embryogenesis and oncogenesis. Thus, the proposed experiments use a combination of mammalian 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.
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, causes cancers, including basal cell carcinoma and medulloblastoma. We are investigating the mechanisms by which Hedgehog ciliary signaling occurs in embryonic development and cancer.
| 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 |
| 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 |
| Reiter, Jeremy F; Leroux, Michel R (2017) Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol 18:533-547 |
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