Adult stem cells have the ability to produce new stem cells (self-renewal) as well as differentiated progeny (Knoblich, 2008;Morrison and Kimble, 2006). Throughout the life of an organism, stem cells are required to proliferate and supply differentiated cells while avoiding the potentially deleterious effects of DNA mutations resulting from repeated cell cycles. It has been hypothesized that stem cells might be accomplishing this remarkable feat by retaining older ("immortal") template DNA strands during asymmetric cell divisions, thereby excluding all replication-induced mutations into the differentiating daughters (Immortal Strand Hypothesis - ISH) (Cairns, 1975). In addition, other models have also been proposed in which stem cells asymmetrically segregate only a subset of chromosome template DNA strands for different reasons, such as retention of epigenetic memories (Armakolas and Klar, 2006). Recently, it was hypothesized by many researchers that the mother centrosome, which is stereotypically retained within some stem cells, might be used as a means to anchor the immortal DNA strands (Tajbakhsh, 2008;Tajbakhsh and Gonzalez, 2009). However, the mechanism and the biological relevance of these chromosome asymmetries remain elusive. This is primarily due to the lack of model systems in which chromosome asymmetries can be assessed in the context of other asymmetries, such as cell fate.
The aim of this research proposal is to study chromosome strand segregation during asymmetric stem cell divisions using the Drosophila melanogaster testis as a model system. Drosophila male germline stem cells (GSCs) offer a unique opportunity to investigate potential chromosome asymmetry, as it is the only system where stereotypical asymmetry in both cell fate and centrosome age is demonstrated (Yamashita et al., 2003;Yamashita et al., 2007). Recently, I have shown that male GSCs in the Drosophila testis do not follow the immortal strand model, despite asymmetrically segregating centrosomes (Yadlapalli et al., 2011). This suggests that GSCs are not asymmetrically segregating the template DNA strands to maintain their genomic integrity. However, there still remains the possibility that GSCs might be asymmetrically segregating only a subset of chromosomes, perhaps to retain epigenetic memories. Strikingly, in my preliminary study I found that GSCs preferentially inherit a certain strand of Y chromosome that is marked by the presence of satellite sequence (AATAC)6, while its complementary strand (GTATT)6 is inherited by the differentiating daughter. Here, I propose to investigate the mechanism and the biological relevance of asymmetric chromosome segregation during GSC division. The proposed research may uncover novel insights into how stem cells might regulate cell fate through asymmetric chromosome distribution. Further, characterization of such mechanisms will allow us to understand how stem cell populations are precisely maintained and regulated to sustain tissue homeostasis, a failure of which might lead to human pathologies including cancers and age-related disorders.

Public Health Relevance

We aim to understand the relevance as well as the mechanism of asymmetric chromosome segregation during stem cell division. Results obtained from the proposed research might provide novel insights into the mechanisms underlying stem cell renewal and differentiation, which can potentially help us understand the role of stem cells in disease and harness their potential in regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HD071727-02
Application #
8459634
Study Section
Special Emphasis Panel (ZRG1-F05-A (20))
Program Officer
Ravindranath, Neelakanta
Project Start
2012-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$32,973
Indirect Cost
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
Yadlapalli, Swathi; Yamashita, Yukiko M (2013) Chromosome-specific nonrandom sister chromatid segregation during stem-cell division. Nature 498:251-4
Yadlapalli, Swathi; Yamashita, Yukiko M (2013) DNA asymmetry in stem cells - immortal or mortal? J Cell Sci 126:4069-76