Centrioles are cellular nanomachines that nucleate and organize centrosomes and cilia. Defects in centrioles contribute to both cancer and ciliopathies. Ciliopathies are a general class of human maladies that include child birth defects, mental retardation, polydactyl, blindness, obesity, and polycystic kidneys. However, the mechanics of centriole formation that, when defective, contribute to the above pathologies are not well understood. Our long term goals are to understand the etiology of such defects. Toward this goal, we will study two important events in centriole formation and function;assembly and stabilization. Both of these events are vital for centrosomes and cilia. An essential centriole structure that is required for both of these events is the cartwheel. To elucidate the molecular assembly of a cartwheel, biochemical, molecular-genetic, and quantitative imaging tactics will be employed. First, we will determine how a novel complex of cartwheel components stabilizes centrioles. Second, we will define how and when protein components interact to build the cartwheel and centriole architecture. Third, one member of the stability complex is Bld10/Cep135 that, in addition to its stability role, is essential for centriole assembly. Bld10's roles in centriole function will be determined by separating its functions in centriole assembly and maintenance and identifying the proteins it interacts with to perform these functions. We will establish the key proteins and the mechanisms for cartwheel and centriole assembly into a stable structure. Building on this stable structure, we can then define how this platform nucleates cilia and centrosomes. This proposal will develop our long term goals to reconstitute cartwheel and centriole assembly and to understand how defects in these processes cause human disease. Our studies will be carried out by a collaborative group of researchers. These studies will provide excellent training experiences for undergraduate and graduate students and postdoctoral researchers and professional research assistants. Collaborations with other labs that include computational modeling, quantitative image analysis, and proteomics will expand the impact of our studies.

Public Health Relevance

Centrioles are required to build centrosomes and cilia that are important for chromosome segregation, cell signaling, and extracellular fluid movement. Defects in centrosomes and cilia cause devastating human diseases, including cancer, obesity, polycystic kidneys, respiratory illness, blindness, and mental retardation. Our research aims to discover the etiology of such maladies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM099820-03
Application #
8706906
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Biology
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Hudish, Laura I; Galati, Domenico F; Ravanelli, Andrew M et al. (2016) miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling. Development 143:2292-304
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Garcia 3rd, Galo; Finnigan, Gregory C; Heasley, Lydia R et al. (2016) Assembly, molecular organization, and membrane-binding properties of development-specific septins. J Cell Biol 212:515-29
Galati, Domenico F (2016) Pkd Proteins Team Up to Tell Cilia Which Way to Go. J Neurosci 36:643-5
Ruehle, Marisa D; Orias, Eduardo; Pearson, Chad G (2016) Tetrahymena as a Unicellular Model Eukaryote: Genetic and Genomic Tools. Genetics 203:649-65
Galati, Domenico F; Abuin, David S; Tauber, Gabriel A et al. (2015) Automated image analysis reveals the dynamic 3-dimensional organization of multi-ciliary arrays. Biol Open 5:20-31
Bayless, Brian A; Galati, Domenico F; Pearson, Chad G (2015) Tetrahymena basal bodies. Cilia 5:1
Dahl, Kristin D; Sankaran, Divya Ganapathi; Bayless, Brian A et al. (2015) A Short CEP135 Splice Isoform Controls Centriole Duplication. Curr Biol 25:2591-6
Galati, Domenico F (2014) During tangential migration, SDF1 lends the cytoskeleton a guiding hand. J Neurosci 34:11868-9

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