Cell and Developmental Biology University of Michigan

Adult stem cells continuously supply highly differentiated but short-lived cells, such as blood, skin, intestinal epithelium, and sperm cells, throughout life. The daughters of stem cell division have two possible fates: stem cell self-renewal or commitment to differentiation. It is critical to maintain a balance between these cell populations as an excess of stem cell self-renewal can lead to tumorgenesis, whereas an excess of differentiation can deplete the stem cell pool, reducing tissue regenerative capacity. To maintain the balance between stem cells and differentiating cells, many stem cells have the potential to divide asymmetrically so that each division produces one stem cell and one differentiating cell. Although the control of stem cell division is crucial for tissue homeostasis, the mechanisms that regulate asymmetric stem cell division are poorly understood. Furthermore, it has been hypothesized that declining stem cell function contributes to tissue degeneration during aging, although the mechanism by which this occurs and whether it involves changes in stem cell division is unknown. Our laboratory is investigating the molecular and cellular mechanisms that govern stem cell behavior, in particular, the regulation of asymmetric stem cell division, using Drosophila male germline stem cells (GSCs) as a model system.

Drosophila male germ line stem cells serve as an ideal model system to study stem cell behavior. They reside in the stem cell niche, which specify stem cell identity by sending signal(s). Stem cells have elaborate cellular mechanisms to ensure the asymmetric outcome of the division, producing one stem cell and one differentiating cell, which is the key to tissue homeostasis. We have discovered the cellular mechanisms by which stem cell divide asymmetrically; one such mechanism is depicted above: The mother centrosome (red and green) is maintained close to the Niche (blue line)-Stem cell (dotted line) interface, while daughter centrosome (red but not green) migrates away from the niche. Such stereotyped behavior of centrosomes prepares the orientation of mitotic spindle in germ line stem cells, so that stem cells always divide perpendicularly to the niche, placing one daughter within and the other outside the niche.

We are also interested in how the centrosome behavior is regulated during the process of aging, leading to a decline in spermatogenesis.

Publications

Representative Publications

Current Research

Cheng J, Turkel N, Hemati N, Fuller MT, Hunt AJ, Yamashita, Y. M.. Nature. 2008 Oct 15. Centrosome misorientation reduces stem cell division during ageing. PubMed Link

Yamashita, YM, Fuller, MT. Asymmetric centrosome behavior and the mechanisms of stem cell division. J Cell Biol.. 2008 Jan 28; 180(2):261-6. Epub 2008 Jan 21. Review. Article (html)

Yamashita, YM. Selfish Stem Cells Compete with Each Other. Cell Stem Cell. Vol 2, 3-4, 10 January 2008. Cell Stem Cell Abstract

Yamashita YM, Mahowald AP, Perlin JR, Fuller MT. Asymmetric inheritance of mother versus daughter centrosome in st em cell division. Science. 2007 Jan 26;315(5811):518-21. Article (pdf) and featured mention (pdf)

Yamashita, Y. M., & Fuller, M. T. (2005). Asymmetric stem cell division and function of the niche in the Drosophila male germ line. International Journal of Hematology, 82, 377-380. PubMed Link

Yamashita, Y. M., Fuller, M. T., & Jones, D. L. (2005). Signaling in stem cell niches: Lessons from the Drosophila germline. Journal of Cell Science, 118, 665-672. PubMed Link

Schulz, C., Kiger, A. A., Tazuke, S. I., Yamashita, Y. M., Pantalena, L. C., Jones, D. L., Wood, C. G., & Fuller, M. T. (2004). A misexpression screen reveals effects of bag-of-marbles and TGF beta class signaling on the Drosophila male germ-line stem cell lineage. Genetics, 167, 707-723. PubMed Link

Yamashita, Y. M., Jones, D. L., & Fuller, M. T. (2003). Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science, 301, 1547-1550. PubMed Link

Other Publications

Hirano, S., Yamamoto, K., Ishiai, M., Yamazoe, M., Seki, M., Matsushita, N., Ohzeki, M., Yamashita, Y. M., Arakawa, H., Buerstedde, J. M., Enomoto, T., Takeda, S., Thompson, L. H., & Takata, M. (2005). Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM. EMBO Journal, 24, 418-427. PubMed Link

Kawamoto, T., Araki, K., Sonoda, E., Yamashita, Y. M., Harada, K., Kikuchi, K., Masutani, C., Hanaoka, F., Nozaki, K., Hashimoto, N., & Takeda, S. (2005). Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Molecular Cell, 20, 793-799. PubMed Link

Jaspers, N. G. J., Raams, A., Kelner, M. J., Ng, J. M. Y., Yamashita, Y. M., Takeda, S., McMorris, T. C., & Hoeijmakers, J. H. J. (2002). Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways. DNA Repair, 1, 1027-1038. PubMed Link

Yamashita, Y. M., Okada, T., Matsusaka, T., Sonoda, E., Zhao, G. Y., Araki, K., Tateishi, S., Yamaizumi, M., & Takeda, S. (2002). RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells. EMBO Journal, 21, 5558-5566. PubMed Link

Okada, T., Sonoda, E., Yamashita, Y. M., Koyoshi, S., Tateishi, S., Yamaizumi, M., Takata, M., Ogawa, O., & Takeda, S. (2002). Involvement of vertebrate Pol kappa in Rad18-independent post-replication repair of UV damage. Journal of Biological Chemistry, 277, 48690-48695. PubMed Link

Sonoda, E., Morrison, C., Yamashita, Y. M., Takata, M., & Takeda, S. (2001). Reverse genetic studies of homologous DNA recombination using the chicken B-lymphocyte line, DT40. Philosophical Transactions of the Royal Society of London (Biological Sciences), 356, 111-117. PubMed Link

Sonoda, E., Takata, M., Yamashita, Y. M., Morrison, C., & Takeda, S. (2001). Homologous DNA recombination in vertebrate cells. Proceedings of the National Academy of Sciences of the USA, 98, 8388-8394. PubMed Link

Yamaguchi-Iwai, Y., Sonoda, E., Sasaki, M. S., Morrison, C., Haraguchi, T., Hiraoka, Y., Yamashita, Y. M., Yagi, T., Takata, M., Price, C., Kakazu, N., & Takeda, S. (1999). Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells. EMBO Journal, 18, 6619-6629. PubMed Link

Yamashita, Y. M., Nakaseko, Y., Kumada, K., Nakagawa, T., & Yanagida, M. (1999). Fission yeast APC/cyclosome subunits, Cut20/Apc4 and Cut23/Apc8, in regulating metaphase-anaphase progression and cellular stress responses. Genes to Cells, 4, 445-463. PubMed Link

Yanagida, M., Yamashita, Y. M., Tatebe, H., Ishii, K., Kumada, K., & Nakaseko, Y. (1999). Control of metaphase-anaphase progression by proteolysis: Cyclosome function regulated by the protein kinase A pathway, ubiquitination and localization. Philosophical Transactions of the Royal Society of London (Biological Sciences), 354, 1559-1569. PubMed Link

Nabeshima, K., Nakagawa, T., Straight, A. F., Murray, A., Chikashige, Y., Yamashita, Y. M., Hiraoka, Y., & Yanagida, M. (1998). Dynamics of centromeres during metaphase-anaphase transition in fission yeast: Dis1 is implicated in force balance in metaphase bipolar spindle. Molecular Biology of the Cell, 9, 3211-3225. PubMed Link

Saitoh, S., Takahashi, K., Nabeshima, K., Yamashita, Y., Nakaseko, Y., Hirata, A., & Yanagida, M. (1996). Aberrant mitosis in fission yeast mutants defective in fatty acid synthetase and acetyl-CoA carboxylase. Journal of Cell Biology, 134, 949-961. PubMed Link

Yamashita, Y. M., Nakaseko, Y., Samejima, I., Kumada, K., Yamada, H., Michaelson, D., & Yanagida, M. (1996). 20S cyclosome complex formation and proteolytic activity inhibited by the cAMP/PKA pathway. Nature, 384, 276-279. PubMed Link

Saka, Y., Sutani, T., Yamashita, Y., Saitoh, S., Takeuchi, M., Nakaseko, Y., & Yanagida, M. (1994). Fission yeast Cut3 and Cut14, members of an ubiquitous protein family, are required for chromosome condensation and segregation in mitosis. EMBO Journal, 13, 4938-4952. PubMed Link