The long-term goal of our research is to address fundamental questions in stem cell biology: how quantity, quality, and activity of stem cells are precisely controlled in vivo. Stem cells are defined by their unique potential to self-renew and to differentiate into mature cell types, which support normal development and maintain tissue homeostasis. Stem cells typically reside in specialized microenvironments called ‘niches’ that support their ability to self-renew and to retain the characteristics of a stem cell. The niche is usually composed of supporting niche cells, extracellular substrates, and signaling molecules that control stem cell activity. For the future advancement of regenerative medicine and the development of novel cancer therapies, it is critical to understand the molecular basis underlying stem cell control by the niche. To understand fundamental principles of stem cell regulation in the extracellular environment, we focus on the role of heparan sulfate proteoglycans (HSPGs) in stem cell control using the genetically tractable model organism Drosophila. HSPGs are a special type of carbohydrate-modified proteins that play an essential role in signaling and distribution of various growth factors, including (but not limited to) bone morphogenetic proteins, Wnt/Wingless, and Hedgehog. Genetic studies of Drosophila stem cells, with sophisticated cell lineage tracing techniques, have helped define basic principles of stem cell biology. Using powerful Drosophila stem cell model systems, we seek to elucidate the cellular and molecular basis for poorly understood stem cell behaviors, including stem cell competition, replacement, and tissue regeneration.
Selected Publications: PubMed
Nakato, E., Bowden, N., and Nakato, H. (2021) Generation of Drosophila heparan sulfate mutant cell lines from existing fly strains. Methods Mol. Biol. 2303:627-636. (Eds. by Balagurunathan, K., Nakato, H., Saijoh, Y., and Desai, U., Springer New York)
Bowden, N., Takemura, M. and Nakato, H. (2021) Molecular genetic techniques for the proteoglycan functions in Drosophila. Methods Mol. Biol. 2303:405-414. (Eds. by Balagurunathan, K., Nakato, H., Saijo, Y., and Desai, U., Springer New York)
Bowden, N. and Nakato, H. (2021) Heparan Sulfate Proteoglycans in the Stem Cell Niche: Lessons from Drosophila. Proteoglycans in stem cells: From development to cancer, Biology of Extracellular Matrix 9, 1-19. (Eds. by Götte, M. and Forsberg-Nilsson, K., Springer Nature)
Takemura, M., Lu, Y.-S., Nakato, E., and Nakato, H. (2021) Endogenous epitope tagging of a JAK/STAT ligand Unpaired1 in Drosophila. MicroPubl. Biol. 10.17912/micropub.biology.000387.
Takemura, M.*, Bowden, N.*, Lu, Y.-S., Nakato, E., O’Connor, M.B., and Nakato, H. (2021) Drosophila MOV10 regulates the termination of midgut regeneration. *These authors contributed equally. Genetics 218(1):iyab031.
Takemura, M., Noborn, F., Nilsson, J., Bowden, N., Nakato, E., Baker, S., Su, T.-Y., Larson, G., and Nakato, H. (2020) Chondroitin sulfate proteoglycan Windpipe modulates Hedgehog signaling in Drosophila. Mol. Biol. Cell 31, 813-824.
Nakato, E., Liu, X., Eriksson, I., Yamamoto, M., Kinoshita-Toyoda, A., Toyoda, H., Kjellén, L., Li, J-P., and Nakato, H. (2019) Establishment and characterization of Drosophila cell lines mutant for heparan sulfate modifying enzymes. Glycobiology 29, 479–489.
Su, T.Y., Nakato, E., Choi, P.Y., and Nakato, H. (2018) Drosophila glypicans regulate follicle stem cell maintenance and niche competition. Genetics 209, 537-549.
Kanai, M.I., Kim, M-J. Akiyama, T., Takemura, M., Wharton, K., O'Connor, M.B. and Nakato, H. (2018) Regulation of neuroblast proliferation by surface glia in the Drosophila larval brain. Sci. Reports 8, 3730.
Levings, D. and Nakato, H. (2018) Loss of heparan sulfate in the niche leads to tumor-like germ cell growth in the Drosophila testis. Glycobiology 28, 32-41.
Tiemeyer, M., Nakato, H. and Esko, J.D. (2017) Chapter 26, Arthropoda in "Essentials of Glycobiology" (3rd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015-2017. Chapter 26.)
Takemura, M. and Nakato, H. (2017) Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration. J. Cell Sci. 130, 332-343.
Nakato, H. and Li, J-P. (2016) Functions of heparan sulfate proteoglycans in development: insights from Drosophila models. Int. Rev. Cell Mol. Biol. 325, 275-293.
Levings, D., Arashiro, T. and Nakato, H. (2016) Heparan sulfate regulates the number and centrosome positioning of Drosophila male germline stem cells. Mol. Biol. Cell 27, 888-896.
Takemura, M. and Nakato, H. (2015) Genetic approaches in the study of heparan sulfate functions in Drosophila. Methods Mol. Biol. 1229, 497-505. (co-edited by Balagurunathan, K., Nakato, H., and Desai, U., Springer New York)
Nakato, H. (2015) Heparan Sulfate Proteoglycans in the Drosophila Ovarian Germline Stem Cell Niche. Glycoscience: Biology and Medicine 825-832. (Eds.,Taniguchi, N., Endo, T., Hart, G., Seeberger, P., Wong, C.-H., Springer, USA)
Dejima, K., Takemura, M., Nakato, E., Peterson, J., Hayashi, Y., Kinoshita-Toyoda, A., Toyoda, H., and Nakato, H. (2013) Analysis of Drosophila glucuronyl C-5 epimerase: implications for developmental roles of heparan sulfate sulfation compensation and 2-O sulfated glucuronic acid. J. Biol. Chem. 288: 34384-93.
Dejima, K., Kleinschmit, A., Takemura, M., Choi, P.Y., Kinoshita-Toyoda, A., Toyoda, H., and Nakato, H. (2013) The role of Drosophila heparan sulfate 6-O endosulfatase in sulfation compensation. J. Biol. Chem. 288: 6574-82.
Kleinschmit, A. Takemura, M., Dejima, K., Choi, P.Y., and Nakato, H. (2013) Drosophila heparan sulfate 6-O endosulfatase Sulf1 facilitates Wingless degradation. J. Biol. Chem. 288: 5081-9.
Hayashi, Y.*, Sexton, TR.*, Dejima, K., Perry, DW., Takemura, M., Kobayashi, S., Nakato, H.§, and Harrison, DA.§ (2012) Glypicans regulate JAK/STAT signaling and distribution of the Unpaired morphogen. *These authors contributed equally. §Co-corresponding authors. Development 139: 4162-71.
Dejima, K., Kanai, M.I., Akiyama, T., Levings, D., and Nakato, H. (2011) Novel contact-dependent bone morphogenetic protein (BMP) signaling mediated by heparan sulfate proteoglycans. J. Biol. Chem. 286: 17103-11.
Wojcinski, A., Nakato, H., Soula, C., and Glise, B. (2011) DSulfatase-1 fine-tunes Hedgehog patterning activity through a novel regulatory feedback loop. Dev Biol. 358, 168-80.
Kamimura, K., Maeda, N., and Nakato, H. (2011) In vivo manipulation of heparan sulfate structure and its effect on Drosophila development. Glycobiology. 21, 607-18.
Kleinschmit, A., Koyama, T., Dejima, K., Hayashi, Y., Kamimura, K., and Nakato H. (2010) Drosophila heparan sulfate 6-O endosulfatase regulates Wingless morphogen gradient formation. Dev. Biol. 345: 204-14.
Hayashi, Y., Kobayashi, S., and Nakato, H. (2009) Drosophila glypicans regulate the germline stem cell niche. J. Cell Biol. 187: 473-80.