Transcriptional/Translational Regulation of Mammalian Spermatogenic Stem Cells

  • Cathryn A. HogarthEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 786)


A fundamental feature of mammalian spermatogenesis is the continuous production of sperm within the testis throughout an animal’s entire reproductive lifetime. It takes many weeks for a single spermatogonial stem cell (SSC) to become a functional sperm yet it has been estimated that the human testis produces 1,000 sperm with each heartbeat or about 37 billion sperm per year [1]. To achieve and sustain this immense level of production, the pool of SSCs and the commitment of these cells to differentiation must be carefully coordinated. Like many other organ stem cell populations, very little is known about the factors that regulate the balance between SSC self-renewal and their commitment to spermatogenesis within the testis. This chapter will review our current understanding of the characteristics of mammalian SSCs and the transcriptional and translational controls governing SSC self-renewal and differentiation. I will focus predominantly on rodent models, as they have generated the majority of data in this field, however, where possible I will also comment on the regulation of SSC pools in other species.


Germ cell niche miRNA Spermatogenesis Spermatogonial stem cells Testis 



A single


A paired


A aligned


days post partum


embryonic day






primordial germ cells


retinoic acid


spermatogonial stem cell



The author would like to acknowledge the help of Christopher Small and Michael Griswold for their critical reading and editing of the chapter.


  1. 1.
    Wade N (2004) Sperm stem cells are grown outside body. The New York Times Company, New YorkGoogle Scholar
  2. 2.
    Ying Y, Qi X, Zhao GQ (2001) Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc Natl Acad Sci USA 98:7858–7862PubMedCrossRefGoogle Scholar
  3. 3.
    Ginsburg M, Snow MH, McLaren A (1990) Primordial germ cells in the mouse embryo during gastrulation. Development 110:521–528PubMedGoogle Scholar
  4. 4.
    McCarrey JR (1993) Development of the germ cell. In: Despardins C, Ewing L (eds) Cell and molecular biology of the testis. Oxford University Press, New YorkGoogle Scholar
  5. 5.
    Bendel-Stenzel M, Anderson R, Heasman J, Wylie C (1998) The origin and migration of primordial germ cells in the mouse. Semin Cell Dev Biol 9:393–400PubMedCrossRefGoogle Scholar
  6. 6.
    Adams IR, McLaren A (2002) Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. Development 129:1155–1164PubMedGoogle Scholar
  7. 7.
    McLaren A (1981) The fate of germ cells in the testis of fetal Sex-reversed mice. J Reprod Fertil 61:461–467PubMedCrossRefGoogle Scholar
  8. 8.
    McLaren A, Southee D (1997) Entry of mouse embryonic germ cells into meiosis. Dev Biol 187:107–113PubMedCrossRefGoogle Scholar
  9. 9.
    Kluin PM, de Rooij DG (1981) A comparison between the morphology and cell kinetics of gonocytes and adult type undifferentiated spermatogonia in the mouse. Int J Androl 4:475–493PubMedCrossRefGoogle Scholar
  10. 10.
    Western PS, Miles DC, van den Bergen JA, Burton M, Sinclair AH (2008) Dynamic regulation of mitotic arrest in fetal male germ cells. Stem Cells 26:339–347PubMedCrossRefGoogle Scholar
  11. 11.
    Cooke HJ, Saunders PT (2002) Mouse models of male infertility. Nat Rev Genet 3:790–801PubMedCrossRefGoogle Scholar
  12. 12.
    Yoshida S, Sukeno M, Nakagawa T, Ohbo K, Nagamatsu G, Suda T, Nabeshima Y (2006) The first round of mouse spermatogenesis is a distinctive program that lacks the self-renewing spermatogonia stage. Development 133:1495–1505PubMedCrossRefGoogle Scholar
  13. 13.
    Oatley JM, Brinster RL (2008) Regulation of spermatogonial stem cell self-renewal in mammals. Ann Rev Cell Dev Biol 24:263–286CrossRefGoogle Scholar
  14. 14.
    Nakagawa T, Sharma M, Nabeshima Y, Braun RE, Yoshida S (2010) Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 328:62–67PubMedCrossRefGoogle Scholar
  15. 15.
    Yoshida S, Nabeshima Y, Nakagawa T (2007) Stem cell heterogeneity: actual and potential stem cell compartments in mouse spermatogenesis. Ann N Y Acad Sci 1120:47–58PubMedCrossRefGoogle Scholar
  16. 16.
    Morimoto H, Kanatsu-Shinohara M, Takashima S, Chuma S, Nakatsuji N, Takehashi M, Shinohara T (2009) Phenotypic plasticity of mouse spermatogonial stem cells. PLoS One 4:e7909PubMedCrossRefGoogle Scholar
  17. 17.
    Hogarth CA, Griswold MD (2010) The key role of vitamin A in spermatogenesis. J Clin Invest 120:956–962PubMedCrossRefGoogle Scholar
  18. 18.
    Ehmcke J, Wistuba J, Schlatt S (2006) Spermatogonial stem cells: questions, models and perspectives. Hum Reprod Update 12:275–282PubMedCrossRefGoogle Scholar
  19. 19.
    Ehmcke J, Schlatt S (2006) A revised model for spermatogonial expansion in man: lessons from non-human primates. Reproduction 132:673–680PubMedCrossRefGoogle Scholar
  20. 20.
    Clermont Y, Bustos-Obregon E (1968) Re-examination of spermatogonial renewal in the rat by means of seminiferous tubules mounted “in toto”. Am J Anat 122:237–247PubMedCrossRefGoogle Scholar
  21. 21.
    Dym M, Clermont Y (1970) Role of spermatogonia in the repair of the seminiferous epithelium following x-irradiation of the rat testis. Am J Anat 128:265–282PubMedCrossRefGoogle Scholar
  22. 22.
    Clermont Y, Hermo L (1975) Spermatogonial stem cells in the albino rat. Am J Anat 142:159–175PubMedCrossRefGoogle Scholar
  23. 23.
    Oatley MJ, Kaucher AV, Racicot KE, Oatley JM (2011) Inhibitor of DNA binding 4 is expressed selectively by single spermatogonia in the male germline and regulates the self-renewal of spermatogonial stem cells in mice. Biol Reprod 85:347–356PubMedCrossRefGoogle Scholar
  24. 24.
    Brinster RL, Zimmermann JW (1994) Spermato­genesis following male germ-cell transplantation. Proc Natl Acad Sci USA 91:11298–11302PubMedCrossRefGoogle Scholar
  25. 25.
    Buaas FW, Kirsh AL, Sharma M, McLean DJ, Morris JL, Griswold MD, de Rooij DG, Braun RE (2004) Plzf is required in adult male germ cells for stem cell self-renewal. Nat Genet 36:647–652PubMedCrossRefGoogle Scholar
  26. 26.
    Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M, Orwig KE, Wolgemuth DJ, Pandolfi PP (2004) Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36:653–659PubMedCrossRefGoogle Scholar
  27. 27.
    Oatley MJ, Racicot KE, Oatley JM (2011) Sertoli cells dictate spermatogonial stem cell niches in the mouse testis. Biol Reprod 84:639–645PubMedCrossRefGoogle Scholar
  28. 28.
    Viglietto G, Dolci S, Bruni P, Baldassarre G, Chiariotti L, Melillo RM, Salvatore G, Chiappetta G, Sferratore F, Fusco A, Santoro M (2000) Glial cell line-derived neutrotrophic factor and neurturin can act as paracrine growth factors stimulating DNA synthesis of Ret-expressing spermatogonia. Int J Oncol 16:689–694PubMedGoogle Scholar
  29. 29.
    Dettin L, Ravindranath N, Hofmann MC, Dym M (2003) Morphological characterization of the spermatogonial subtypes in the neonatal mouse testis. Biol Reprod 69:1565–1571PubMedCrossRefGoogle Scholar
  30. 30.
    Ebata KT, Zhang X, Nagano MC (2005) Expression patterns of cell-surface molecules on male germ line stem cell during postnatal mouse development. Mol Reprod Dev 72:171–178PubMedCrossRefGoogle Scholar
  31. 31.
    He Z, Jiang J, Hofmann MC, Dym M (2007) Gfra1 silencing in mouse spermatogonial stem cells results in their differentiation via the inactivation of RET tyrosine kinase. Biol Reprod 77:723–733PubMedCrossRefGoogle Scholar
  32. 32.
    Kubota H, Avarbock MR, Brinster RL (2003) Spermatogonial stem cells share some, but not all, phenotypic and functinoal characteristics with other stem cells. Proc Natl Acad Sci USA 100:6487–6492PubMedCrossRefGoogle Scholar
  33. 33.
    Pesce M, Wang X, Wolgemuth DJ, Scholer H (1998) Differential expression of the Oct-4 transcription factor during mouse germ cell differentiation. Mech Dev 71:89–98PubMedCrossRefGoogle Scholar
  34. 34.
    Yoshida S, Takakura A, Ohbo K, Abe K, Wakabayashi J, Yamamoto M, Suda T, Nabeshima Y (2004) Neurogenin3 delineates the earliest stages of spermatogenesis in the mouse testis. Dev Biol 269:447–458PubMedCrossRefGoogle Scholar
  35. 35.
    Sada A, Suzuki A, Suzuki H, Saga Y (2009) The RNA-binding protein NANOS2 is required to maintain murine spermatogonial stem cells. Science 325:1394–1398PubMedCrossRefGoogle Scholar
  36. 36.
    Suzuki H, Sada A, Yoshida S, Saga Y (2009) The heterogeneity of spermatogonia is revealed by their topology and expression of marker proteins including the germ cell-specific proteins Nanos2 and Nanos3. Dev Biol 336:222–231PubMedCrossRefGoogle Scholar
  37. 37.
    Ballow DJ, Xin Y, Choi Y, Pangas SA, Rajkovic A (2006a) Sohlh2 is a germ cell-specific bHLH transcription factor. Gene Expr Patterns 6:1014–1018PubMedCrossRefGoogle Scholar
  38. 38.
    Ballow D, Meistrich ML, Matzuk M, Rajkovic A (2006b) Sohlh1 is essential for spermatogonial differentiation. Dev Biol 294:161–167PubMedCrossRefGoogle Scholar
  39. 39.
    Tegelenbosch RA, de Rooij DG (1993) A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101F1 hybrid mouse. Mutat Res 290:193–200PubMedCrossRefGoogle Scholar
  40. 40.
    Kubota H, Avarbock MR, Brinster RL (2004) Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells. Proc Natl Acad Sci USA 101:16489–16494PubMedCrossRefGoogle Scholar
  41. 41.
    Oatley JM, Avarbock MR, Telaranta AI, Fearon DT, Brinster RL (2006) Identifying genes important for spermatogonial stem cell self-renewal and survival. Proc Natl Acad Sci USA 103:9524–9529PubMedCrossRefGoogle Scholar
  42. 42.
    Kokkinaki M, Lee TL, He Z, Jiang J, Golestaneh N, Hofmann MC, Chan WY, Dym M (2010) Age affects gene expression in mouse spermatogonial stem/progenitor cells. Reproduction 139:1011–1020PubMedCrossRefGoogle Scholar
  43. 43.
    Oatley JM, Oatley MJ, Avarbock MR, Tobias JW, Brinster RL (2009) Colony stimulating factor 1 is an extrinsic stimulator of mouse spermatogonial stem cell self-renewal. Development 136:1191–1199PubMedCrossRefGoogle Scholar
  44. 44.
    Kokkinaki M, Lee TL, He Z, Jiang J, Golestaneh N, Hofmann MC, Chan WY, Dym M (2009) The molecular signature of spermatogonial stem/progenitor cells in the 6-day-old mouse testis. Biol Reprod 80:707–717PubMedCrossRefGoogle Scholar
  45. 45.
    Orwig KE, Ryu BY, Master SR, Phillips BT, Mack M, Avarbock MR, Chodosh L, Brinster RL (2008) Genes involved in post-transcriptional regulation are overrepresented in stem/progenitor spermatogonia of cryptorchid mouse testes. Stem Cells 26:927–938PubMedCrossRefGoogle Scholar
  46. 46.
    Schmidt JA, Avarbock MR, Tobias JW, Brinster RL (2009) Identification of glial cell line-derived neurotrophic factor-regulated genes important for spermatogonial stem cell self-renewal in the rat. Biol Reprod 81:56–66PubMedCrossRefGoogle Scholar
  47. 47.
    von Kopylow K, Kirchhoff C, Jezek D, Schulze W, Feig C, Primig M, Steinkraus V, Spiess AN (2010) Screening for biomarkers of spermatogonia within the human testis: a whole genome approach. Hum Reprod 25:1104–1112CrossRefGoogle Scholar
  48. 48.
    Niu Z, Goodyear SM, Rao S, Wu X, Tobias JW, Avarbock MR, Brinster RL (2011) MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells. Proc Natl Acad Sci USA 108:12740–12745PubMedCrossRefGoogle Scholar
  49. 49.
    Tong MH, Mitchell DA, McGowan SD, Evanoff R, Griswold MD (2012) Two miRNA Clusters, Mir-17-92 (Mirc1) and Mir-106b-25 (Mirc3), are involved in the regulation of spermatogonial differentiation in mice. Biol Reprod 86:72PubMedCrossRefGoogle Scholar
  50. 50.
    Shinohara T, Avarbock MR, Brinster RL (2000) Functional analysis of spermatogonial stem cells in Steel and cryptorchid infertile mouse models. Dev Biol 220:401–411PubMedCrossRefGoogle Scholar
  51. 51.
    Barna M, Merghoub T, Costoya JA, Ruggero D, Branford M, Bergia A, Samori B, Pandolfi PP (2002) Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. Dev Cell 3:499–510PubMedCrossRefGoogle Scholar
  52. 52.
    Filipponi D, Hobbs RM, Ottolenghi S, Rossi P, Jannini EA, Pandolfi PP, Dolci S (2007) Repression of kit expression by Plzf in germ cells. Mol Cell Biol 27:6770–6781PubMedCrossRefGoogle Scholar
  53. 53.
    Hobbs RM, Seandel M, Falciatori I, Rafii S, Pandolfi PP (2010) Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell 142:468–479PubMedCrossRefGoogle Scholar
  54. 54.
    Payne C, Braun RE (2006) Histone lysine trimethylation exhibits a distinct perinuclear distribution in Plzf-expressing spermatogonia. Dev Biol 293:461–472PubMedCrossRefGoogle Scholar
  55. 55.
    Mohapatra C, Barman HK, Panda RP, Kumar S, Das V, Mohanta R, Mohapatra SD, Jayasankar P (2010) Cloning of cDNA and prediction of peptide structure of Plzf expressed in the spermatogonial cells of Labeo rohita. Mar Genomics 3:157–163PubMedCrossRefGoogle Scholar
  56. 56.
    Ozaki Y, Saito K, Shinya M, Kawasaki T, Sakai N (2011) Evaluation of Sycp3, Plzf and Cyclin B3 expression and suitability as spermatogonia and spermatocyte markers in zebrafish. Gene Expr Patterns 11:309–315PubMedCrossRefGoogle Scholar
  57. 57.
    Buageaw A, Sukhwani M, Ben-Yehudah A, Ehmcke J, Rawe VY, Pholpramool C, Orwig KE, Schlatt S (2005) GDNF family receptor alpha1 phenotype of spermatogonial stem cells in immature mouse testes. Biol Reprod 73:1011–1016PubMedCrossRefGoogle Scholar
  58. 58.
    Naughton CK, Jain S, Strickland AM, Gupta A, Milbrandt J (2006) Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol Reprod 74:314–321PubMedCrossRefGoogle Scholar
  59. 59.
    Jijiwa M, Kawai K, Fukihara J, Nakamura A, Hasegawa M, Suzuki C, Sato T, Enomoto A, Asai N, Murakumo Y, Takahashi M (2008) GDNF-mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells. Genes Cells 13:365–374PubMedCrossRefGoogle Scholar
  60. 60.
    Grisanti L, Falciatori I, Grasso M, Dovere L, Fera S, Muciaccia B, Fuso A, Berno V, Boitani C, Stefanini M, Vicini E (2009) Identification of spermatogonial stem cell subsets by morphological analysis and prospective isolation. Stem Cells 27:3043–3052PubMedGoogle Scholar
  61. 61.
    Grasso M, Fuso A, Dovere L, de Rooij DG, Stefanini M, Boitani C, Vicini E (2012) Distribution of GFRA1-expressing spermatogonia in adult mouse testis. Reproduction 143:325–332PubMedCrossRefGoogle Scholar
  62. 62.
    Yoshida S, Sukeno M, Nabeshima Y (2007) A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317:1722–1726PubMedCrossRefGoogle Scholar
  63. 63.
    Wang C, Lehmann R (1991) Nanos is the localized posterior determinant in Drosophila. Cell 66:637–647PubMedCrossRefGoogle Scholar
  64. 64.
    Tsuda M, Sasaoka Y, Kiso M, Abe K, Haraguchi S, Kobayashi S, Saga Y (2003) Conserved role of nanos proteins in germ cell development. Science 301:1239–1241PubMedCrossRefGoogle Scholar
  65. 65.
    Sonoda J, Wharton RP (2001) Drosophila brain tumor is a translational repressor. Genes Dev 15:762–773PubMedCrossRefGoogle Scholar
  66. 66.
    Kadyrova LY, Habara Y, Lee TH, Wharton RP (2007) Translational control of maternal Cyclin B mRNA by Nanos in the Drosophila germline. Development 134:1519–1527PubMedCrossRefGoogle Scholar
  67. 67.
    Lolicato F, Marino R, Paronetto MP, Pellegrini M, Dolci S, Geremia R, Grimaldi P (2008) Potential role of Nanos3 in maintaining the undifferentiated spermatogonia population. Dev Biol 313:725–738PubMedCrossRefGoogle Scholar
  68. 68.
    Saga Y (2010) Function of Nanos2 in the male germ cell lineage in mice. Cell Mol Life Sci 67:3815–3822PubMedCrossRefGoogle Scholar
  69. 69.
    Julaton VT, Reijo Pera RA (2011) NANOS3 function in human germ cell development. Hum Mol Genet 20:2238–2250PubMedCrossRefGoogle Scholar
  70. 70.
    Sada A, Hasegawa K, Pin PH, Saga Y (2012) NANOS2 acts downstream of glial cell line-derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells. Stem Cells 30:280–291PubMedCrossRefGoogle Scholar
  71. 71.
    Barrios F, Filipponi D, Pellegrini M, Paronetto MP, Di Siena S, Geremia R, Rossi P, De Felici M, Jannini EA, Dolci S (2010) Opposing effects of retinoic acid and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells. J Cell Sci 123:871–880PubMedCrossRefGoogle Scholar
  72. 72.
    Riechmann V, van Cruchten I, Sablitzky F (1994) The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3. Nucleic Acids Res 22:749–755PubMedCrossRefGoogle Scholar
  73. 73.
    Sun XH, Copeland NG, Jenkins NA, Baltimore D (1991) Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol Cell Biol 11:5603–5611PubMedGoogle Scholar
  74. 74.
    Sablitzky F, Moore A, Bromley M, Deed RW, Newton JS, Norton JD (1998) Stage- and subcellular-specific expression of Id proteins in male germ and Sertoli cells implicates distinctive regulatory roles for Id proteins during meiosis, spermatogenesis, and Sertoli cell function. Cell Growth Differ 9:1015–1024PubMedGoogle Scholar
  75. 75.
    Oatley JM, Brinster RL (2012) The germline stem cell niche unit in mammalian testes. Physiol Rev 92:577–595PubMedCrossRefGoogle Scholar
  76. 76.
    Hofmann MC (2008) Gdnf signaling pathways within the mammalian spermatogonial stem cell niche. Mol Cell Endocrinol 288:95–103PubMedCrossRefGoogle Scholar
  77. 77.
    Mullaney BP, Skinner MK (1992) Basic fibroblast growth factor (bFGF) gene expression and protein production during pubertal development of the seminiferous tubule: follicle-stimulating hormone-induced Sertoli cell bFGF expression. Endocrinology 131:2928–2934PubMedCrossRefGoogle Scholar
  78. 78.
    Spinnler K, Kohn FM, Schwarzer U, Mayerhofer A (2010) Glial cell line-derived neurotrophic factor is constitutively produced by human testicular peritubular cells and may contribute to the spermatogonial stem cell niche in man. Hum Reprod 25:2181–2187PubMedCrossRefGoogle Scholar
  79. 79.
    Meng X, Lindahl M, Hyvonen ME, Parvinen M, de Rooij DG, Hess MW, Raatikainen-Ahokas A, Sainio K, Rauvala H, Lakso M, Pichel JG, Westphal H et al (2000) Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287:1489–1493PubMedCrossRefGoogle Scholar
  80. 80.
    Kanatsu-Shinohara M, Ogonuki N, Inoue K, Miki H, Ogura A, Toyokuni S, Shinohara T (2003) Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Biol Reprod 69:612–616PubMedCrossRefGoogle Scholar
  81. 81.
    Nagano M, Ryu BY, Brinster CJ, Avarbock MR, Brinster RL (2003) Maintenance of mouse male germ line stem cells in vitro. Biol Reprod 68:2207–2214PubMedCrossRefGoogle Scholar
  82. 82.
    Braydich-Stolle L, Kostereva N, Dym M, Hofmann MC (2007) Role of Src family kinases and N-Myc in spermatogonial stem cell proliferation. Dev Biol 304:34–45PubMedCrossRefGoogle Scholar
  83. 83.
    Oatley JM, Avarbock MR, Brinster RL (2007) Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling. J Biol Chem 282:25842–25851PubMedCrossRefGoogle Scholar
  84. 84.
    Lee J, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Kimura T, Nakano T, Ogura A, Shinohara T (2007) Akt mediates self-renewal division of mouse spermatogonial stem cells. Development 134:1853–1859PubMedCrossRefGoogle Scholar
  85. 85.
    Encinas M, Crowder RJ, Milbrandt J, Johnson EM Jr (2004) Tyrosine 981, a novel ret autophosphorylation site, binds c-Src to mediate neuronal survival. J Biol Chem 279:18262–18269PubMedCrossRefGoogle Scholar
  86. 86.
    He Z, Jiang J, Kokkinaki M, Golestaneh N, Hofmann MC, Dym M (2008) Gdnf upregulates c-Fos transcription via the Ras/Erk1/2 pathway to promote mouse spermatogonial stem cell proliferation. Stem Cells 26:266–278PubMedCrossRefGoogle Scholar
  87. 87.
    Pellegrini M, Grimaldi P, Rossi P, Geremia R, Dolci S (2003) Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation. J Cell Sci 116:3363–3372PubMedCrossRefGoogle Scholar
  88. 88.
    Mithraprabhu S, Mendis S, Meachem SJ, Tubino L, Matzuk MM, Brown CW, Loveland KL (2010) Activin bioactivity affects germ cell differentiation in the postnatal mouse testis in vivo. Biol Reprod 82:980–990PubMedCrossRefGoogle Scholar
  89. 89.
    Hamra FK, Chapman KM, Nguyen D, Garbers DL (2007) Identification of neuregulin as a factor required for formation of aligned spermatogonia. J Biol Chem 282:721–730PubMedCrossRefGoogle Scholar
  90. 90.
    Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30PubMedCrossRefGoogle Scholar
  91. 91.
    Oral O, Uchida I, Eto K, Nakayama Y, Nishimura O, Hirao Y, Ueda J, Tarui H, Agata K, Abe S (2008) Promotion of spermatogonial proliferation by neuregulin 1 in newt (Cynops pyrrhogaster) testis. Mech Dev 125:906–917PubMedCrossRefGoogle Scholar
  92. 92.
    Zhou Q, Li Y, Nie R, Friel P, Mitchell D, Evanoff RM, Pouchnik D, Banasik B, McCarrey JR, Small C, Griswold MD (2008) Expression of stimulated by retinoic acid gene 8 (Stra8) and maturation of murine gonocytes and spermatogonia induced by retinoic acid in vitro. Biol Reprod 78:537–545PubMedCrossRefGoogle Scholar
  93. 93.
    Hogarth CA, Evanoff R, Snyder E, Kent T, Mitchell D, Small C, Amory JK, Griswold MD (2011) Suppression of Stra8 expression in the mouse gonad by WIN 18,446. Biol Reprod 84:957–965PubMedCrossRefGoogle Scholar
  94. 94.
    Snyder EM, Small C, Griswold MD (2010) Retinoic acid availability drives the asynchronous initiation of spermatogonial differentiation in the mouse. Biol Reprod 83(5):783–790PubMedCrossRefGoogle Scholar
  95. 95.
    Snyder EM, Davis JC, Zhou Q, Evanoff R, Griswold MD (2011) Exposure to retinoic acid in the neonatal but not adult mouse results in synchronous spermatogenesis. Biol Reprod 84:886–893PubMedCrossRefGoogle Scholar
  96. 96.
    Pellegrini M, Filipponi D, Gori M, Barrios F, Lolicato F, Grimaldi P, Rossi P, Jannini EA, Geremia R, Dolci S (2008) ATRA and KL promote differentiation toward the meiotic program of male germ cells. Cell Cycle 7:3878–3888PubMedCrossRefGoogle Scholar
  97. 97.
    Shinohara T, Avarbock MR, Brinster RL (1999) beta1- and alpha6-integrin are surface markers on mouse spermatogonial stem cells. Proc Natl Acad Sci USA 96:5504–5509PubMedCrossRefGoogle Scholar
  98. 98.
    Kanatsu-Shinohara M, Takehashi M, Takashima S, Lee J, Morimoto H, Chuma S, Raducanu A, Nakatsuji N, Fassler R, Shinohara T (2008) Homing of mouse spermatogonial stem cells to germline niche depends on beta1-integrin. Cell Stem Cell 3:533–542PubMedCrossRefGoogle Scholar
  99. 99.
    Chiarini-Garcia H, Hornick JR, Griswold MD, Russell LD (2001) Distribution of type A spermatogonia in the mouse is not random. Biol Reprod 65:1179–1185PubMedCrossRefGoogle Scholar
  100. 100.
    Chiarini-Garcia H, Raymer AM, Russell LD (2003) Non-random distribution of spermatogonia in rats: evidence of niches in the seminiferous tubules. Reproduction 126:669–680PubMedCrossRefGoogle Scholar
  101. 101.
    He Z, Kokkinaki M, Pant D, Gallicano GI, Dym M (2009) Small RNA molecules in the regulation of spermatogenesis. Reproduction 137:901–911PubMedCrossRefGoogle Scholar
  102. 102.
    Shomron N, Levy C (2009) MicroRNA-biogenesis and Pre-mRNA splicing crosstalk. J Biomed Biotechnol 2009:594678PubMedGoogle Scholar
  103. 103.
    Hayashi K, Chuva de Sousa Lopes SM, Kaneda M, Tang F, Hajkova P, Lao K, O’Carroll D, Das PP, Tarakhovsky A, Miska EA, Surani MA (2008) MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS One 3:e1738PubMedCrossRefGoogle Scholar
  104. 104.
    Papaioannou MD, Pitetti JL, Ro S, Park C, Aubry F, Schaad O, Vejnar CE, Kuhne F, Descombes P, Zdobnov EM, McManus MT, Guillou F et al (2009) Sertoli cell Dicer is essential for spermatogenesis in mice. Dev Biol 326:250–259PubMedCrossRefGoogle Scholar
  105. 105.
    Maatouk DM, Loveland KL, McManus MT, Moore K, Harfe BD (2008) Dicer1 is required for differentiation of the mouse male germline. Biol Reprod 79:696–703PubMedCrossRefGoogle Scholar
  106. 106.
    Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139PubMedCrossRefGoogle Scholar
  107. 107.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854PubMedCrossRefGoogle Scholar
  108. 108.
    Buchold GM, Coarfa C, Kim J, Milosavljevic A, Gunaratne PH, Matzuk MM (2010) Analysis of microRNA expression in the prepubertal testis. PLoS One 5:e15317PubMedCrossRefGoogle Scholar
  109. 109.
    Jung YH, Gupta MK, Shin JY, Uhm SJ, Lee HT (2010) MicroRNA signature in testes-derived male germ-line stem cells. Mol Hum Reprod 16:804–810PubMedCrossRefGoogle Scholar
  110. 110.
    Ro S, Park C, Sanders KM, McCarrey JR, Yan W (2007) Cloning and expression profiling of testis-expressed microRNAs. Dev Biol 311:592–602PubMedCrossRefGoogle Scholar
  111. 111.
    Shin JY, Gupta MK, Jung YH, Uhm SJ, Lee HT (2011) Differential genomic imprinting and expression of imprinted microRNAs in testes-derived male germ-line stem cells in mouse. PLoS One 6:e22481PubMedCrossRefGoogle Scholar
  112. 112.
    Tong MH, Mitchell D, Evanoff R, Griswold MD (2011) Expression of Mirlet7 family microRNAs in response to retinoic acid-induced spermatogonial differentiation in mice. Biol Reprod 85:189–197PubMedCrossRefGoogle Scholar
  113. 113.
    Mclver SC, Stanger SJ, Santarelli DM, Roman SD, Nixon B, McLaughlin EA (2012) A unique combination of male germ cell miRNAs coordinates gonocyte differentiation. PLoS One 7:e35553CrossRefGoogle Scholar
  114. 114.
    Chen C, Ouyang W, Grigura V, Zhou Q, Carnes K, Lim H, Zhao GQ, Arber S, Kurpios N, Murphy TL, Cheng AM, Hassell JA et al (2005) ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436:1030–1034PubMedCrossRefGoogle Scholar
  115. 115.
    Zheng J, Xue H, Wang T, Jiang Y, Liu B, Li J, Liu Y, Wang W, Zhang B, Sun M (2011) miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion. J Cell Biochem 112:872–880PubMedCrossRefGoogle Scholar
  116. 116.
    Gillis AJ, Stoop HJ, Hersmus R, Oosterhuis JW, Sun Y, Chen C, Guenther S, Sherlock J, Veltman I, Baeten J, van der Spek PJ, de Alarcon P et al (2007) High-throughput microRNAome analysis in human germ cell tumours. J Pathol 213:319–328PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.School of Molecular Biosciences and the Centre for Reproductive BiologyWashington State UniversityPullmanUSA

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