Many cells in the human body possess a singular projection from their surface called a primary cilium. Although the existence of primary cilia has been recognized for over a century, only recently has it become clear that they function in the detection and interpretation of important intercellular cues. Some of these cues, such as Hedgehog signals, are key regulators of embryonic patterning and adult tissue homeostasis. Consequently, defects in Hedgehog signaling can cause birth defects and some forms of cancer. Similarly, defects in primary cilia can cause rare congenital syndromes such as Meckel and Joubert syndromes, may underlie more common human diseases such as polycystic kidney disease, and are important for the progression of some cancers. Mammalian cells with ciliary defects fail to respond to Hedgehog signals. We have found that some tissues are ciliated at specific times in development, and within adult tissues, some cells can be ciliated and others not. We hypothesize that the control of which cells are ciliated shapes how tissues respond to cilium-interpreted signals. We have recently identified a class of novel genes called the Tectonics, which support ciliogenesis in some tissues and control ciliary membrane composition in others. The Tectonics interact and co-localize with ciliary disease proteins at a subdomain of the cilium called the transition zone. We propose to study Tectonics and their interactors to understand the tissue-specific regulation of ciliary functions. Specifically, we will answer three complementary questions: 1) Do different Tectonics regulate ciliogenesis in different tissues? 2) Do Tectonics and other transition zone components promote ciliogenesis by regulating protein transport to the cilium? 3) Do Tectonics function with human disease genes, such as those underlying Meckel syndrome and polycystic kidney disease, to regulate ciliogenesis? The proposed experiments combine genetic, imaging and biochemical approaches to provide answers to these questions. This work will elucidate the mechanism by which Tectonics and associated proteins contribute to ciliary function, providing molecular and cell biological insights into how cilia function in development and how they misfunction in human ciliopathies.

Public Health Relevance

Primary cilia are small projections found on many human cells involved in receiving and interpreting signals from other cells. Disruption of these ciliary signaling events contributes to birth defects, cancer, polycystic kidney disease, and other human disorders. We propose to investigate the mechanisms controlling cilium formation and protein composition to provide a molecular understanding of cilia-related diseases.)

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Krasnewich, Donna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
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

Showing the most recent 10 out of 30 publications