Regulatory Mechanisms of the Germline Stem Cell Niche in Drosophila melanogaster

Part of the Diversity and Commonality in Animals book series (DCA)


Stem cells possess the unique ability to produce both self-renewing and differentiating daughter cells continuously throughout an animal’s lifespan. Understanding the mechanisms that regulate proper stem cell maintenance is a central issue in basic biology and medical science. Since the stem cell niche hypothesis arose in the late 1970s, it has been widely believed that stem cells are maintained within a specialized extracellular microenvironment known as the niche. Germline stem cells (GSCs) in the fruit fly, Drosophila melanogaster, provide an excellent model for study of the stem cell niche in vivo. The first molecular components constituting the Drosophila ovarian GSC niche were identified in 1998. Since that time, identification of niche components and our understanding of how the niche maintains stem cells have continued to progress. In this review, we introduce how the niche maintains GSCs, as well as how the niche itself is precisely formed in the tissue. In addition, we discuss recent findings showing that the state of the host organism, including nutrient status and aging, affects niche function and stem cell maintenance.


Germline stem cell Drosophila melanogaster Stem cell niche Extracellular matrix Heparan sulfate proteoglycan Glypican Aging Nutrient condition 



The authors apologize to researchers whose pertinent work could not be cited due to space limitations. Research in our laboratory is supported by a Grant-in-Aid for Scientific Research (KAKENHI) on Innovative Areas (#26116730), KAKENHI for Young Scientists (A) (#25711020) to Y.H., and KAKENHI on Innovative Areas (#25114002) to S. K.


  1. Akiyama T, Kamimura K, Firkus C, Takeo S, Shimmi O, Nakato H (2008) Dally regulates Dpp morphogen gradient formation by stabilizing Dpp on the cell surface. Dev Biol 313:408–419CrossRefPubMedGoogle Scholar
  2. Asaoka M, Lin H (2004) Germline stem cells in the Drosophila ovary descend from pole cells in the anterior region of the embryonic gonad. Development (Cambridge, England) 131:5079–5089CrossRefGoogle Scholar
  3. Boyle M, Wong C, Rocha M, Jones DL (2007) Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1:470–478CrossRefPubMedGoogle Scholar
  4. Chen D, McKearin D (2003) Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells. Curr Biol 13:1786–1791CrossRefPubMedGoogle Scholar
  5. Decotto E, Spradling AC (2005) The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev Cell 9:501–510CrossRefPubMedGoogle Scholar
  6. Dinardo S, Okegbe T, Wingert L, Freilich S, Terry N (2011) lines and bowl affect the specification of cyst stem cells and niche cells in the Drosophila testis. Development (Camb Engl) 138:1687–1696CrossRefGoogle Scholar
  7. Drummond-Barbosa D, Spradling AC (2001) Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev Biol 231:265–278CrossRefPubMedGoogle Scholar
  8. Fujise M, Takeo S, Kamimura K, Matsuo T, Aigaki T, Izumi S, Nakato H (2003) Dally regulates Dpp morphogen gradient formation in the Drosophila wing. Development (Cambr Engl) 130:1515–1522CrossRefGoogle Scholar
  9. Guo Z, Wang Z (2009) The glypican Dally is required in the niche for the maintenance of germline stem cells and short-range BMP signaling in the Drosophila ovary. Development (Cambr Engl) 136:3627–3635CrossRefGoogle Scholar
  10. Hacker U, Nybakken K, Perrimon N (2005) Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol 6:530–541CrossRefPubMedGoogle Scholar
  11. Hayashi Y, Kobayashi S, Nakato H (2009) Drosophila glypicans regulate the germline stem cell niche. J Cell Biol 187:473–480CrossRefPubMedPubMedCentralGoogle Scholar
  12. Hayashi Y, Sexton TR, Dejima K, Perry DW, Takemura M, Kobayashi S, Nakato H, Harrison DA (2012) Glypicans regulate JAK/STAT signaling and distribution of the Unpaired morphogen. Development (Cambr Engl) 139:4162–4171CrossRefGoogle Scholar
  13. Hsu HJ, Drummond-Barbosa D (2009) Insulin levels control female germline stem cell maintenance via the niche in Drosophila. Proc Natl Acad Sci U S A 106:1117–1121CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hsu HJ, Drummond-Barbosa D (2011) Insulin signals control the competence of the Drosophila female germline stem cell niche to respond to Notch ligands. Dev Biol 350:290–300CrossRefPubMedGoogle Scholar
  15. Inaba M, Buszczak M, Yamashita YM (2015) Nanotubes mediate niche-stem-cell signalling in the Drosophila testis. Nature 523:329–332CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kawase E, Wong MD, Ding BC, Xie T (2004) Gbb/Bmp signaling is essential for maintaining germline stem cells and for repressing bam transcription in the Drosophila testis. Development (Cambr Engl) 131:1365–1375CrossRefGoogle Scholar
  17. Kiger AA, White-Cooper H, Fuller MT (2000) Somatic support cells restrict germline stem cell self-renewal and promote differentiation. Nature 407:750–754CrossRefGoogle Scholar
  18. Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT (2001) Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294:2542–2545CrossRefPubMedGoogle Scholar
  19. Kitadate Y, Kobayashi S (2010) Notch and Egfr signaling act antagonistically to regulate germ-line stem cell niche formation in Drosophila male embryonic gonads. Proc Natl Acad Sci U S A 107:14241–14246CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kitadate Y, Shigenobu S, Arita K, Kobayashi S (2007) Boss/Sev signaling from germline to soma restricts germline-stem-cell-niche formation in the anterior region of Drosophila male gonads. Dev Cell 13:151–159CrossRefPubMedGoogle Scholar
  21. LaFever L, Drummond-Barbosa D (2005) Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science 309:1071–1073CrossRefPubMedGoogle Scholar
  22. Le Bras S, Van Doren M (2006) Development of the male germline stem cell niche in Drosophila. Dev Biol 294:92–103CrossRefPubMedGoogle Scholar
  23. Leatherman JL, Dinardo S (2010) Germline self-renewal requires cyst stem cells and stat regulates niche adhesion in Drosophila testes. Nat Cell Biol 12:806–811CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lim JG, Fuller MT (2012) Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in Drosophila testes. Proc Natl Acad Sci U S A 109:18477–18481CrossRefPubMedPubMedCentralGoogle Scholar
  25. Lin G, Xu N, Xi R (2008) Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature 455:1119–1123CrossRefPubMedGoogle Scholar
  26. Morris LX, Spradling AC (2011) Long-term live imaging provides new insight into stem cell regulation and germline-soma coordination in the Drosophila ovary. Development (Cambridge, England) 138:2207–2215CrossRefGoogle Scholar
  27. Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M et al (2015) Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 21:392–402CrossRefPubMedGoogle Scholar
  28. Pan L, Chen S, Weng C, Call G, Zhu D, Tang H, Zhang N, Xie T (2007) Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 1:458–469CrossRefPubMedGoogle Scholar
  29. Prasad M, Jang AC, Starz-Gaiano M, Melani M, Montell DJ (2007) A protocol for culturing Drosophila melanogaster stage 9 egg chambers for live imaging. Nat Protoc 2:2467–2473CrossRefPubMedGoogle Scholar
  30. Rojas-Rios P, Guerrero I, Gonzalez-Reyes A (2012) Cytoneme-mediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. PLoS Biol 10:e1001298CrossRefPubMedPubMedCentralGoogle Scholar
  31. Roth TM, Chiang CY, Inaba M, Yuan H, Salzmann V, Roth CE, Yamashita YM (2012) Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells. Mol Biol Cell 23:1524–1532CrossRefPubMedPubMedCentralGoogle Scholar
  32. Roy S, Huang H, Liu S, Kornberg TB (2014) Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein. Science 343:1244624CrossRefPubMedPubMedCentralGoogle Scholar
  33. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7–25PubMedGoogle Scholar
  34. Sheng XR, Matunis E (2011) Live imaging of the Drosophila spermatogonial stem cell niche reveals novel mechanisms regulating germline stem cell output. Development (Cambridge, England) 138:3367–3376CrossRefGoogle Scholar
  35. Sheng XR, Posenau T, Gumulak-Smith JJ, Matunis E, Van Doren M, Wawersik M (2009) Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis. Dev Biol 334:335–344CrossRefPubMedPubMedCentralGoogle Scholar
  36. Shiraki N, Shiraki Y, Tsuyama T, Obata F, Miura M, Nagae G, Aburatani H, Kume K, Endo F, Kume S (2014) Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab 19:780–794CrossRefPubMedGoogle Scholar
  37. Song X, Xie T (2002) DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc Natl Acad Sci U S A 99:14813–14818CrossRefPubMedPubMedCentralGoogle Scholar
  38. Song X, Wong MD, Kawase E, Xi R, Ding BC, McCarthy JJ, Xie T (2004) Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development (Cambr Engl) 131:1353–1364CrossRefGoogle Scholar
  39. Song X, Call GB, Kirilly D, Xie T (2007) Notch signaling controls germline stem cell niche formation in the Drosophila ovary. Development (Cambr Engl) 134:1071–1080CrossRefGoogle Scholar
  40. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M et al (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7:391–402CrossRefPubMedGoogle Scholar
  41. Tulina N, Matunis E (2001) Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 294:2546–2549CrossRefPubMedGoogle Scholar
  42. Uryu O, Ameku T, Niwa R (2015) Recent progress in understanding the role of ecdysteroids in adult insects: Germline development and circadian clock in the fruit fly Drosophila melanogaster. Zool Lett 1:32CrossRefGoogle Scholar
  43. Voog J, D’Alterio C, Jones DL (2008) Multipotent somatic stem cells contribute to the stem cell niche in the Drosophila testis. Nature 454:1132–1136CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wallenfang MR, Nayak R, DiNardo S (2006) Dynamics of the male germline stem cell population during aging of Drosophila melanogaster. Aging Cell 5:297–304CrossRefPubMedGoogle Scholar
  45. Wang X, Harris RE, Bayston LJ, Ashe HL (2008) Type IV collagens regulate BMP signalling in Drosophila. Nature 455:72–77CrossRefPubMedGoogle Scholar
  46. Xie T, Spradling AC (1998) decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell 94:251–260CrossRefPubMedGoogle Scholar
  47. Xie T, Spradling AC (2000) A niche maintaining germ line stem cells in the Drosophila ovary. Science 290:328–330CrossRefPubMedPubMedCentralGoogle Scholar
  48. Yoshida S, Sukeno M, Nabeshima Y (2007) A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317:1722–1726CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA)University of TsukubaTsukubaJapan

Personalised recommendations