Stem cells continuously produce highly differentiated but short-lived cells, such as blood, skin, intestinal epithelium, and sperm cells throughout life. Asymmetric stem cell division, which produces one self-renewed stem cell and one differentiated cell, plays a critical role in maintaining tissue homeostasis.
The aim of this research proposal is to investigate the molecular and cellular mechanisms that govern stem cell behavior, in particular, the regulation of asymmetric stem cell division, using Drosophila male germ line stem cells (GSCs) as a model system. We have previously shown that centrosome orientation within GSCs with respect to the niche plays a central role in asymmetric GSC division. Our preliminary results suggest the existence of a checkpoint mechanism that monitors correct centrosome orientation within GSCs, ensuring an asymmetric outcome of stem cell division. We will characterize this checkpoint (referred to as the "orientation checkpoint") and aim to identify the components of the checkpoint mechanism. We will investigate at which cell cycle stage the checkpoint arrests/delays the GSC cell cycle in response to centrosome misorientation. We will also take a candidate approach to identify the components of the orientation checkpoint. Furthermore, we will investigate the potential role of this checkpoint mechanism in the age-related decline in tissue regenerative capacity.
We aim to understand the mechanisms by which adult stem cells ensure to maintain both stem cell and differentiated cell populations. Understanding of such mechanisms may allow us to manipulate stem cell behavior;for example, normal stem cells can be expanded in culture for transplantation, or we can inhibit the expansion of cancerous stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086481-04
Application #
8204759
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hamlet, Michelle R
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$287,709
Indirect Cost
$101,490
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Shields, Alicia R; Spence, Allyson C; Yamashita, Yukiko M et al. (2014) The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells. Development 141:73-82
Yuan, Hebao; Chiang, C-Y Ason; Cheng, Jun et al. (2012) Regulation of cyclin A localization downstream of Par-1 function is critical for the centrosome orientation checkpoint in Drosophila male germline stem cells. Dev Biol 361:57-67
Inaba, Mayu; Yuan, Hebao; Yamashita, Yukiko M (2011) String (Cdc25) regulates stem cell maintenance, proliferation and aging in Drosophila testis. Development 138:5079-86
Cheng, Jun; Tiyaboonchai, Amita; Yamashita, Yukiko M et al. (2011) Asymmetric division of cyst stem cells in Drosophila testis is ensured by anaphase spindle repositioning. Development 138:831-7
Pereira, Gislene; Yamashita, Yukiko M (2011) Fly meets yeast: checking the correct orientation of cell division. Trends Cell Biol 21:526-33
Yadlapalli, Swathi; Cheng, Jun; Yamashita, Yukiko M (2011) Drosophila male germline stem cells do not asymmetrically segregate chromosome strands. J Cell Sci 124:933-9
Yamashita, Yukiko M (2010) Cell adhesion in regulation of asymmetric stem cell division. Curr Opin Cell Biol 22:605-10
Yamashita, Yukiko M; Yuan, Hebao; Cheng, Jun et al. (2010) Polarity in stem cell division: asymmetric stem cell division in tissue homeostasis. Cold Spring Harb Perspect Biol 2:a001313
Yuan, Hebao; Yamashita, Yukiko M (2010) Germline stem cells: stems of the next generation. Curr Opin Cell Biol 22:730-6
Inaba, Mayu; Yuan, Hebao; Salzmann, Viktoria et al. (2010) E-cadherin is required for centrosome and spindle orientation in Drosophila male germline stem cells. PLoS One 5:e12473

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