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.)

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095941-02
Application #
8303407
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Krasnewich, Donna M
Project Start
2011-07-18
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$290,460
Indirect Cost
$102,460
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
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de la Roche, Maike; Ritter, Alex T; Angus, Karen L et al. (2013) Hedgehog signaling controls T cell killing at the immunological synapse. Science 342:1247-50
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
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