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 cause congenital syndromes such as Meckel and Joubert syndromes, can underlie more common human diseases such as polycystic kidney disease, and are essential for the progression of some cancers. To function in signaling, primary cilia need to maintain a different composition than surrounding parts of the cell. We identified the transition zone, a region of the ciliary base, as a critical regulator of ciliary composition. To understand how the transition zone controls which proteins localize to cilia, we will answer three complementary questions. First, given that the transition zone is a complex and highly structured region of the cilium, we will determine how it is built. Identifying the architecture of the transition zone and how it is disrupted by ciliopathy mutations will provide structural insights into the origins of ciliary signaling defects. Second, we will examine whether the transition zone regulates protein entry into the cilium, exit from the cilium, or acts as a diffusion barrier at the ciliary base. Understanding how different components impart different characteristics to the transition zone will help reveal how this gate controls ciliary composition. Third, we will examine how different complexes cooperate within the transition zone to support ciliogenesis and ciliary signaling. These experiments will help elucidate how mutations in different transition zone components result in different developmental phenotypes, both in mice and humans. By elucidating the mechanisms by which the transition zone controls ciliary composition, we will understand how the cell compartmentalizes this organelle to perform critical signaling functions during mammalian development.

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 will investigate how cells control which signaling proteins are at cilia to provide a mechanistic understanding of the origins of cilia-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM095941-05
Application #
8961124
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Krasnewich, Donna M
Project Start
2011-07-18
Project End
2019-04-30
Budget Start
2015-07-10
Budget End
2016-04-30
Support Year
5
Fiscal Year
2015
Total Cost
$404,414
Indirect Cost
$144,414
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; Raleigh, David R; Reiter, Jeremy F (2018) How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In. Curr Biol 28:R421-R434
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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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