Centriole orientation and positioning are critical for the functions of centrioles, including the nucleation of motile cilia capable of generating coherent fluid flows in the proper direction, sensory cilia capable of sensing conditions at the appropriate location in a tissue, and positioning of mitotic spindles in the correct orientation during oriented cell division. However, the mechanisms that position and orient centrioles are almost completely unknown. The proposed experiments will explore the mechanisms that determine centriole position, using an integrated combination of genetic, proteomic, and imaging approaches. By identifying and analyzing genes with specific roles in centriole orientation and positioning, we hope to learn whether the different degrees of freedom of centriole orientation are independently regulated, and by what pathways;how centriole position relates to centriole duplication;and how individual elements of the centriole proteome contribute to centriole orientation. We expect that the genes thus uncovered would potentially constitute a new class of ciliary disease genes in which cilia form normally and retain normal function, but are located in the wrong position or beat in the wrong direction.

Public Health Relevance

Centrioles are cylinder-shaped structures within the cell, and have been implicated in a host of human diseases including cancer and polycystic kidney disease. Our studies will investigate the pathways required to form these structures in the correct position, revealing a new set of candidate disease genes involved in regulating centriole orientation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077004-07
Application #
8305469
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
2006-03-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
7
Fiscal Year
2012
Total Cost
$288,190
Indirect Cost
$98,190
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
Ishikawa, Hiroaki; Ide, Takahiro; Yagi, Toshiki et al. (2014) TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella. Elife 3:e01566
Ishikawa, Hiroaki; Marshall, Wallace F (2013) Isolation of mammalian primary cilia. Methods Enzymol 525:311-25
Apte, Zachary S; Marshall, Wallace F (2013) Statistical method for comparing the level of intracellular organization between cells. Proc Natl Acad Sci U S A 110:E1006-15
Ishikawa, Hiroaki; Thompson, James; Yates 3rd, John R et al. (2012) Proteomic analysis of mammalian primary cilia. Curr Biol 22:414-9
Azimzadeh, Juliette; Wong, Mei Lie; Downhour, Diane Miller et al. (2012) Centrosome loss in the evolution of planarians. Science 335:461-3
Tang, Nan; Marshall, Wallace F; McMahon, Martin et al. (2011) Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science 333:342-5
Rafelski, Susanne M; Keller, Lani C; Alberts, Jonathan B et al. (2011) Apparent diffusive motion of centrin foci in living cells: implications for diffusion-based motion in centriole duplication. Phys Biol 8:026010
Azimzadeh, Juliette; Marshall, Wallace F (2010) Building the centriole. Curr Biol 20:R816-25
Keller, Lani C; Wemmer, Kimberly A; Marshall, Wallace F (2010) Influence of centriole number on mitotic spindle length and symmetry. Cytoskeleton (Hoboken) 67:504-18
Marshall, Wallace F (2009) Centriole evolution. Curr Opin Cell Biol 21:14-9

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