Smads and cell fate: Distinct roles in specification, development, and tumorigenesis in the testis

IUBMB Life

Volumn 65, Issue 2, 2013, Pages 85-97

  Itman, Catherine ^a   Loveland, Kate L ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

activin; bone morphogenetic protein; development; germ cell; sertoli; spermatogenesis; stem cell; transforming growth factor beta

Indexed keywords

ACTIVIN A; BONE MORPHOGENETIC PROTEIN; LIGAND; SMAD PROTEIN; SMAD1 PROTEIN; SMAD2 PROTEIN; SMAD3 PROTEIN; SMAD4 PROTEIN; SMAD5 PROTEIN; SMAD6 PROTEIN; SMAD7 PROTEIN; SMAD8 PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

CARCINOGENESIS; CELL FATE; CELL LINEAGE; ECTODERM; EMBRYO DEVELOPMENT; FETUS DEVELOPMENT; HUMAN; MALE FERTILITY; NONHUMAN; PHOTOPERIODICITY; PRIMARY CELL CULTURE; PRIMORDIAL GERM CELL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REPRODUCTIVE HEALTH; REVIEW; SEMINOMA; SERTOLI CELL; SIGNAL TRANSDUCTION; SPERMATOCYTE; SPERMATOGENESIS; SPERMATOGONIUM; TESTIS DEVELOPMENT; TESTIS FUNCTION;

ANIMALS; BODY PATTERNING; CELL TRANSFORMATION, NEOPLASTIC; GERM CELLS; HUMANS; MALE; SIGNAL TRANSDUCTION; SMAD PROTEINS; TESTICULAR NEOPLASMS; TESTIS; TGF-BETA SUPERFAMILY PROTEINS;

EID: 84873852309     PISSN: 15216543     EISSN: 15216551     Source Type: Journal    
DOI: 10.1002/iub.1115     Document Type: Review

References (125)

1. Kandeel, F. R., Swerdloff, R. S., and, Pryor, J. L., (eds.) (2007) Male Reproductive Dysfunction: Pathophysiology and Treatment, Informa Healthcare USA Inc., New York.
2. Tam, P. P., and, Zhou, S. X., (1996) The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo. Dev. Biol. 178, 124-132.
3. Koopman, P., (1999) Sry and Sox9: mammalian testis-determining genes. Cell. Mol. Life Sci. 55, 839-856.
4. Western, P. S., Miles, D. C., van den Bergen, J. A., Burton, M., and, Sinclair, A. H., (2007) Dynamic regulation of mitotic arrest in fetal male germ cells. Stem Cells 26, 339-347.
5. Archambeault, D. R., and, Yao, H. H., (2010) Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion. Proc. Natl. Acad. Sci. U. S. A. 107, 10526-10531.
6. Mendis, S., Meachem, S., Sarraj, M., and, Loveland, K. L., (2010) Activin A balances Sertoli and germ cell proliferation in the fetal mouse testis. Biol. Reprod. 84, 379-391.
7. Hermo, L., Pelletier, R. M., Cyr, D. G., and, Smith, C. E., (2010) Surfing the wave, cycle, life history and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia and spermatocytes. Microsc. Res. Tech. 73, 241-278.
8. Kluin, P. M., Kramer, M. F., and, de Rooij, D. G., (1984) Proliferation of sprematogonia and Sertoli cells in maturing mice. Anat. Embryol. 160, 73-78.
9. Wu, X., Wan, S., and, Lee, M. M., (2007) Key factors in the regulation of fetal and postnatal Leydig cell development. J. Cell. Physiol. 213, 429-433.
10. Feng, X. H., and, Derynck, R., (2005) Specificity and versatility in TGFbeta signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659-693.
11. Massague, J., Seoane, J., and, Wotton, D., (2005) Smad transcription factors. Genes Dev. 19, 2783-2810.
12. Moustakas, A., and, Heldin, C.-H., (2009) The regulation of TGFbeta signal transduction. Development 136, 3699-3714.
13. Cheng, C. Y., (ed.) (2008) Molecular Mechanisms in Spermatogenesis, Landes Bioscience, Austin, TX.
14. de Rooij, D. G., (1998) Stem cells in the testis. Int. J. Exp. Pathol. 79, 67-80.
15. de Rooij, D. G., and, Griswold, M. D., (2012) Questions about spermatogonia posed and answered since 2000. J. Androl. [Epub ahead of print].
16. Oatley, M. J., Racicot, K. E., and, Oatley, J. M., (2011) Sertoli cells dictate spermatogonial stem cell niches in the mouse testis. Biol. Reprod. 84, 639-645.
17. Barakat, B., Itman, C., Mendis, S., and, Loveland, K. L., (2012) Activins and inhibins in mammalian testis development: new models, new insights. Mol. Cell. Endocrinol. 359, 66-77.
18. Chang, H., Brown, C. W., and, Matzuk, M. M., (2002) Genetic analysis of the mammalian Transforming growth factor-beta superfamily. Endocr. Rev. 23, L787-823.
19. Itman, C., Mendis, S., Barakat, B., and, Loveland, K. L., (2006) All in the family: transforming growth factor beta family action in testis development. Reproduction 132, 233-246.
20. Barakat, B., Itman, C., Mendis, S. H., Loveland, K. L., (2012) Activins and inhibins in mammalian testis development: new models, new insights. Mol. Cell. Biol. 359, 66-77.
21. Loveland, K. L., and, Hime, G. R., (2005) TGF-beta superfamily members in spermatogenesis: setting the stage for fertility in the mouse and Drosophila. Cell Tissue Res. 322, 141-146.
22. Shi, Y., and, Massague, J., (2003) Mechanisms of TGF-beta signalling from cell membrane to the nucleus. Cell Adhes. Commun. 113, 685-700.
23. Moustakis, A., and, Heldin, C. H., (2005) Non-Smad TGF-beta signals. J. Cell Sci. 118, 3573-3584.
24. Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H., and, Gelbart, W. M., (1995) Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347-1358.
25. Hahn, S. A., Schutte, M., Hogue, A. T., Moskalk, C. A., da Costa, L. T., et al. (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.2. Science 271, 350-353.
26. Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C.-H., Kern, S. E., et al. (1996) Nomenclature: vertebrate mediators of TGfbeta family signals. Cell 87, 173.
27. Mullen, A. C., Orlando, D. A., Newman, J. J., Loven, J., Kumar, R. M., et al. (2011) Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565-576.
28. Yan, X., and, Chen, Y.-G., (2011) Smad7: not only a regulator, but also a cross-talk mediator of TGFbeta signalling. Biochem. J. 434, 1-10.
29. Bakkebo, M., Huse, K., Hilden, V. I., Smeland, E. B., and, Oksvold, M. P., (2010) TGF-beta-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutively active p38 MAPK. BMC Immunol. 11, 57.
30. Daly, A. C., Randall, R. A., and, Hill, C. S., (2008) Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol. Cell. Biol. 28, 6889-6902.
31. Liu, I. M., Schilling, S. H., Knouse, K. A., Choy, L., Derynck, R., et al. (2008) TGF-beta stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGF-beta switch. EMBO J. 28, 88-98.
32. Barbara, N. P., Wrana, J. L., and, Letarte, M., (1999) Endoglin is an accessory protein that interacts with the signalling receptor comlex of multiple members of the transforming growth factor-beta superfamily. J. Biol. Chem. 274, 584-594.
33. Onichtchouk, D., Chen, Y.-G., Dosch, R., Gawantka, V., Delius, H., et al. (1999) Silencing of TGFbeta signalling by the pseudoreceptor BAMBI. Nature 401, 480-485.
34. Massague, J., (2000) How cells read TGF-beta signals. Nat. Rev. 1, 169-178.
35. Conidi, A., Cazzola, S., Beets, K., Coddens, K., Collart, C., et al. (2011) Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFb/BMP signaling in vivo. Cytokine Growth Factor Rev. 22, 287-300.
36. Matsuzaki, K., (2011) Smad phosphoisoform signaling specificity: the right place at the right time. Carcinogenesis 32, 1578-1588.
37. Dias, V., Meachem, S., Rajpert-de Meyts, E., McLachlan, R., Manuelpillai, U., et al. (2008) Activin receptor subunits in normal and dysfunctional adult human testis. Hum. Reprod. 23, 412-420.
38. Fragale, A., Puglisi, R., Morena, A. R., Stafanini, M., and, Boitani, C., (2001) Age-dependent activin receptor expression pinpoints activin A as a physiological regulator of rat Sertoli cell proliferation. Mol. Hum. Reprod. 7, 1107-1114.
39. Itman, C., and, Loveland, K. L., (2008) SMAD expression in the testis: an insight into BMP regulation of spermatogenesis. Dev. Dyn. 237, 97-111.
40. Itman, C., Wong, C., Hunyadi, B., Ernst, M., Jans, D. A., et al. (2011) Smad3 regulates androgen responsiveness and influences maturation in the juvenile testis. Endocrinology 152, 2076-2089.
41. Wang, R.-A., and, Zhao, G.-Q., (1999) Transforming growth factor beta signal transducer Smad2 is expressed in mouse meiotic germ cells, Sertoli cells and Leydig cells during spermatogenesis. Biol. Reprod. 61, 999-1004.
42. Zhao, G. Q., and, Hogan, B. L. M., (1997) Evidence that mothers-against-dpp-related 1 (Madr1) plays a role in the initiation and maintenance of spermatogenesis in the mouse. Mech. Dev. 61, 63-73.
43. Dias, V. L., Rajpert-de Meyts, E., McLachlan, R., and, Loveland, K. L., (2009) Analysis of activin/TGFb-signaling modulators within the normal and dysfunctinoal adult human testis reveals evidence of altered signaling capacity in a subset of seminomas. Reproduction 138, 801-811.
44. Itman, C., Whiley, P. A., Zhou, W., Meistrich, M. L., Sahin Z,., et al. (2009) Regulated production of SnoN2 is a feature of testicular differentiation. Microsc. Res. Tech. 72, 833-844.
45. Itman, C., Wong, C., Whiley, P. A., Fernando, D., and, Loveland, K. L., (2011) TGF-beta superfamily signalling regulators are differentially expressed in the developing and adult mouse testis. Spermatogenesis 1, 63-72.
46. Arnold, S. J., Maretto, S., Islam, A., Bikoff, E. K., and, Robertson, E. J., (2006) Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo. Dev. Biol. 296, 104-118.
47. Dunn, N. R., Koonce, C. H., Anderson, D. C., Islam, A., Bikoff, E. K., et al. (2005) Mice exclusively expressing the short isoform of Smad2 develop normally and are viable and fertile. Genes Dev. 19, 153-163.
48. Zhu, Y., Richardson, J. A., Parada, L. F., and, Graff, J. M., (1998) Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703-707f714.
49. Aoki, H., Fujii, M., Imamura, T., Yagi, K., Takehara, K., et al. (2001) Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. J. Cell Sci. 114, 1483-1489.
50. Hatakeyama, Y., Nguyen, J., Wang, X., Muckolls, G. H., and, Shum, L., (2003) Smad signaling in mesenchymal and chondroprogenitor cells. J. Bone Joint Surg. Am. 85-A, 13-18.
51. Ying, Y., and, Zhao, G. Q., (2001) Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse. Dev. Biol. 232, 484-492.
52. Hayashi, K., Kobayashi, T., Umino, T., Goitsuka, R., Matsui, Y., et al. (2002) SMAD1 signaling is critical for initial commitment of germ cell lineage from mouse epiblast. Mech. Dev. 118, 99-109.
53. Tremblay, K. D., Dunn, N. R., and, Robertson, E. J., (2001) Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation. Development 128, 3609-3621.
54. Chang, H., and, Matzuk, M. M., (2001) Smad5 is required for mouse primordial germ cell development. Mech. Dev. 104, 61-67.
55. Hayashi, K. K. T., Umino, T., Goitsuka, R., Matsui, Y., and, Kitamura, D., (2002) SMAD1 signaling is critical for initial commitment of germ cell lineage from mouse epiblast. Mech. Dev. 118, 99-109.
56. Chu, G. C., Dunn, N. R., Anderson, D. C., Oxburgh, L., and, Robertson, E. J., (2004) Differential requirements for Smad4 in TGFbeta-dependent patterning of the early mouse embryo. Development 131, 3501-3512.
57. de Sousa Lopes, S. M., Roelen, B. A., Monteiro, R. M., Emmens, R., Lin, H. Y., et al. (2004) BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev. 18, 1839-1849.
58. Matzuk, M. M., Kumar, T. R., Vassalli, A., Bickenbach, J. R., Roop, D. R., et al. (1995) Functional analysis of activins during mammalian development. Nature 1995, 6520.
59. Memon, M. A., Anway, M. D., Covert, T. R., Uzumcu, M., and, Skinner, M. K., (2008) Transforming growth factor beta (TGFb1, TGFb2, TGFb3) null-mutant phenotypes in embryonic gonadal development. Mol. Cell. Endocrinol. 294, 70-80.
60. Richards, A. J., Enders, G. C., and, Resnick, J. L., (1999) Activin and TGF-beta limit murine primordial germ cell proliferation. Dev. Biol. 207, 470-475.
61. Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L., and, Robertson, E. J., (1998) Smad2 signaling in the extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92, 797-808.
62. Li, C.-Y., Guo, Z., and, Wang, Z., (2007) TGFbeta receptor saxophone non-autonomously regulates the germline proliferation in a Smox/dSmad2-dependent manner in Drosophila testis. Dev. Biol. 309, 70-77.
63. Wilhelm, D., Palmer, S., and, Koopman, P., (2007) Sex determination and gonadal development in mammals. Physiol. Rev. 87, 1-28.
64. Boitani, C., Stefanini, M., Fragale, A., and, Morena, A. R., (1995) Activin stimulates Sertoli cell proliferation in a defined period of rat testis development. Endocrinology 136, 4538-5444.
65. Buzzard, J. J., Farnworth, P. G., de Kretser, D. M., O'Connor, A. E., Wreford, N. G., et al. (2003) Proliferative phase Sertoli cells display a developmentally regulated response to activin in vitro. Endocrinology 144, 474-483.
66. Itman, C., Small, C., Griswold, M. D., Nagaraja, A. K., Matzuk, M. M., et al. (2009) Developmentally regulated SMAD2 and SMAD3 utilization directs activin signalling outcomes. Dev. Dyn. 238, 1688-1700.
67. Luukko, K., Ylikorkala, A., and, Makela, T. P., (2001) Developmentally regulated expression of Smad3, Smad4, Smad6 and Smad7involved in TGF-beta signaling. Mech. Dev. 101, 209-212.
68. Moreno, S. G., Attali, M., Allemand, I., Messiaen, S., Fouchet, P., et al. (2010) TGFbeta signaling in male germ cells regulates gonocyte quiescence and fertility in mice. Dev. Biol. 342, 74-84.
69. Souquet, B., Tourpin, S., Messiaen, S., Moison, D., Habert, R., et al. (2012) Nodal signaling regulates the entry into meiosis in fetal germ cells. Endocrinology 153, 2466-2473.
70. Ishisaki, A., Yamato, K., Hashimoto, S., Nakao, A., Tamaki, K., et al. (1999) Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J. Biol. Chem. 274, 13637-13642.
71. Narula, A., Kilen, S., Ma, E., Kroeger, J., Goldberg, E., et al. (2002) Smad4 overexpression causes germ cell ablation and Leydig cell hyperplasia in transgenic mice. Am. J. Pathol. 161, 1723-1734.
72. Barakat, B., O'Connor, A. E., Gold, E., de Kretser, D. M., and, Loveland, K. L., (2008) Inhibin, activin, follistatin and follicle stimulating hormone serum levels and testicular production are highly modulated during the first spermatogenic wave in mice. Reproduction 136, 345-359.
73. Mullaney, B. P., and, Skinner, M. K., (1993) Transforming growth factor-beta (Beta1, Beta2 and Beta3) gene expression and action during pubertal development of the seminiferous tubule: potential role at the onset of spermatogenesis. Mol. Endocrinol. 7, 67-76.
74. Pellegrini, M., Grimaldi, P., Rossi, P., Geremia, R., and, Dolci, S., (2003) Developmental expression of BMP4/ALK3/SMAD5 signalling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation. J. Cell Sci. 116, 3363-3372.
75. Olaso, R., Pairault, C., Boulogne, B., Durand, P., and, Habert, R., (1998) Transforming growth factor beta1 and beta2 reduce the number of gonocytes by increasing apoptosis. Endocrinology 139, 733-740.
76. Mather, J. P., Attie, K. M., Woodruff, T. K., Rice, G. C., and, Phillips, D. M., (1990) Activin stimulates spermatogonial proliferation in germ-Sertoli cell cultures from immature rat testis. Endocrinology 127, 3206-3214.
77. Li, Q., Graff, J. M., O'Connor, A. E., Loveland, K. L., and, Matzuk, M. M., (2007) SMAD3 regulates gonadal tumorigenesis. Mol. Endocrinol. 21, 2472-2486.
78. Pangas, S. A., Li, X., Umans, L., Zwijsen, A., Huylebroeck, D., et al. (2008) Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumour development in mice. Mol. Cell. Biol. 28, 248-257.
79. Zhao, G.-Q., Liaw, L., and, Hogan, B. L. M., (1998) Bone morphogenetic protein 8A plays a role in the maintenance of spermatogenesis and the integrity of the epididymis. Development 125, 1103-1112.
80. Zhao, G. Q., Deng, K., Labosky, P. A., Liaw, L., and, Hogan, B. L. M., (1996) The gene encoding bone morphogenetic protein 8B (BMP8B) is required for the initiation and maintenance of spermatogenesis in the mouse. Genes Dev. 10, 1657-1669.
81. Zhao, G.-Q., Chen, Y.-X., Liu, X.-M., Xu, Z., and, Qi, X., (2001) Mutation in Bmp7 exacerbates the phenotype of Bmp8a mutants in spermatogenesis and epididymis. Dev. Biol. 241, 212-222.
82. Hu, J., Chen, Y.-X., Wang, D., Qi, X., Li T.-G., et al. (2004) Developmental expression and function of Bmp4 in spermatogenesis and in maintaining epididymal integrity. Dev. Biol. 276, 158-171.
83. Kokkinaki, M., Lee, T.-L., He, Z., Jiang, J., Golestaneh, N., et al. (2010) Age affects gene expression in mouse spermatogonial stem/progenitor cells. Reproduction 139, 1011-1020.
84. de Bosscher, K., Hill, C. S., and, Nicolas, F. J., (2004) Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells. Biochem. J. 379, 209-216.
85. Inman, G. J., Nicolas, F. J., and, Hill, C. S., (2002) Nucleocytoplasmic shuttling of Smads 2,3 and 4 permits sensing of TGF-beta receptor activity. Mol. Cell 10, 283-294.
86. Liu, F., Pouponnot, C., and, Massague, J., (1997) Dual role of the Smad4/DPC4 tumor suppressor in TGFb-inducible transcriptional compelxes. Genes Dev. 11, 3157-3167.
87. Itman, C., and, Loveland, K. L., SMAD expression in the testis: an insight into BMP regulation of spermatogenesis. Dev. Dyn. 237, 97-111.
88. Itoh, F., Divecha, N., Brocks, L., Oomen, L., Janssen, H., et al. (2002) The FYVE domain in Smad anchor for receptor activation (SARA) is sufficient for localization of SARA in early endosomes and regulates TGF-beta/Smad signalling. Genes Cells 7, 321-331.
89. Goto, D., Nakajima, N., Mori, Y., Kurasawa, K., Kitamura, N., et al. (2001) Interaction between Smad anchor for receptor activation and Smad3 is not essential for TGFbeta/Smad3 mediated signaling. Biochem. Biophys. Res. Commun. 281, 1100-1105.
90. Runyan, C. E., Schnaper, H. W., and, Poncelet, A. C., (2005) The role of internalization in transforming growth factor beta 1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells. J. Biol. Chem. 289, 8300-8308.
91. Miura, S., Takeshita, T., Asao, H., Kimura, Y., Murata, K., et al. (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol. Cell. Biol. 20, 9346-9355.
92. Xu, J., Beyer, A. R., Walker, W. H., and, McGee, E. A., (2003) Developmental and stage-specific expression of Smad2 and Smad3 in rat testis. J. Androl. 24, 192-200.
93. Bergmann, M., (1987) Photoperiod and testicular function in Phodopus sungorus. Adv. Anat. Embryol. Cell Biol. 105, 1-76.
94. Kano, K., Kurohmaru, M., Hayashi, Y., and, Taniguchi, K., (2001) Effects of short photoperiod on the expression of Smad2 and Smad3 mRNA in Syrian hamster testis. J. Vet. Med. Sci. 63, 25-30.
95. Sheng, X., Zhang, H., Zhang, M., Zhang, W., Hu, X., et al. (2012) Seasonal changes in immunoreactivity of activin signaling component proteins in wild ground squirrel testes. J. Reprod. Dev. 58, 126-131.
96. Rajpert-de Meyts, E., and, Hoei-Hansen, C. E., (2007) From gonocytes to testicular cancer: the role of impaired gonadal development. Ann. N. Y. Acad. Sci. 1120, 168-180.
97. Fustino, N., Rakheja, D., Ateek, C. S., Neumann, J. C., and, Amatruda, J. F., (2011) Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours. Int. J. Androl. 34, e218-e233.
98. Bouras, M., Tabone, E., Bertholon, J., Sommer, P., Bouvier, R., et al. (2000) A novel SMAD4 gene mutation in seminoma germ cell tumors. Cancer Res. 60, 922-928.
99. Looyenga, B. D., and, Hammer, G. D., (2007) Genetic removal of Smad3 from inhibin-null mice attenuates tumor progression by uncoupling extracellular mitogenic signals from the cell cycle machinery. Mol. Endocrinol. 21, 2440-2457.
100. de Jong, J., Stoop, H., Gillis, J. M., Hersmus, R., van Gurp, R. J. H. L. M., et al. (2008) Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer 47, 185-196.
101. Nettersheim, D., Westernstroer, B., Haas, N., Leinhaas, A., Brustle, O., et al. (2012) Establishment of a versatile seminoma model indicates cellular plasticity of germ cell tumour cells. Genes Chromosomes Cancer 51, 717-726.
102. Young, J. C., Jaiprakash, A., Mithraprabhu, S., Itman, C., Kitazawa, R., et al. (2011) TCam-2 seminoma cell line exhibits characteristic foetal germ cell responses to TGF-beta ligands and retinoic acid. Int. J. Androl. 4, E204-e217.
103. Dalgaard, M. D., Weinhold, N., Edsgard, D., Silver, J. D., Pers, T. H., et al. (2012) A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation. J. Med. Genet. 49, 58-65.
104. Cools, M., Wolffenbuttel, K. P., Drop, S. L. S., Oosterhuis, J. W., and, Looijenga, L. H. J., (2011) Gonadal development and tumor formation at the crossroads of male and female sex determination. Sex. Dev. 5, 167-180.
105. National Cancer Institute U.N.I.o.H. (2009) Surveillance Epidemiology and End Results. Available at: www.seer.cancer.gov.
106. Rajpert-de Meyts, E., Toppari, J., Hoi-Hansen, C. E., Muller, J., and, Skakkebaek, N. E., (2003) Testicular Neoplasia in Childhood and Adolescence, Karger Publishing, Basel, Switzerland.
107. Young, R. H., (2005) Sex cord-stromal tumours of the ovary and testis: their similarities and differences with consideration of selected problems. Mod. Pathol. 18, S81-S98.
108. Young, R. H., (2008) Testicular tumours-some new and a few perennial problems. Arch. Pathol. Lab. Med. 132, 548-564.
109. Matzuk, M. M., Finegold, M. J., Su, J. G., Hsueh, A. J., and, Bradley, A., (1992) Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360, 313-319.
110. Rajanahally, S., Agno, J. E., Nalam, R. L., Weinstein, M. B., Loveland, K. L., et al. (2010) Genetic evidence that Smad2 is not required for gonadal tumor development in inhibin-deficient mice. Reprod. Biol. Endocrinol. 8, 69.
111. Griswold, M. D., (1998) The central role of Sertoli cells in spermatogenesis. Semin. Cell Dev. Biol. 9, 411-416.
112. McLachlan, R., O'Donnell, L., Meachem, S., Stanton, P. G., de Kretser, D. M., et al. (2002) Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys and man. Recent Prog. Horm. Res. 57, 149-179.
113. Meachem, S. J., Ruwanpura, S. M., Ziolkowski, J., Ague, J. M., Skinner, M., et al. (2005) Developmentally distinct in vivo effects of FSH on proliferation and apoptosis during testis maturation. J. Endocrinol. 186, 429-446.
114. Krishnamurthy, H., Babu, P. S., Morales, C. R., and, Sairam, M. R., (2001) Delay in sexual maturity of the follicle-stimulating hormone receptor knockout male mouse. Biol. Reprod. 65, 522-531.
115. Wreford, N. G., Kumar, T. R., Matzuk, M. M., and, de Kretser, D. M., (2001) Analysis of the testicular phenotype of the follicle-stimulating hormone beta-subunit knockout and the activin type II receptor knockout mice by stereological analysis. Endocrinology 142, 2916-2920.
116. Kumar, T. R., Palapattu, G., Wang, P., Woodruff, T. K., Boime, I., et al. (1999) Transgenic models to study gonadotropin function: the role of follicle-stimulating hormone in gonadal growth and tumorigenesis. Mol. Endocrinol. 13, 851-865.
117. Kumar, T. R., Wang, Y., and, Matzuk, M. M., (1996) Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice. Endocrinology 137, 4210-4216.
118. Wang, R.-S., Yeh, S., Tzeng, C.-R., and, Chang, C., (2009) Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr. Rev. 30, 119-132.
119. Tan, K., de Gendt, K., Atanassova, N., Walker, M., Sharpe, R., et al. (2005) The role of androgens in Sertoli cell proliferation and functional maturation: studies in mice with total or Sertoli cell-selective ablation of the androgen receptor. Endocrinology 146, 2674-2683.
120. Hwang, K., Yatsenko, A. N., Jorgez, C. J., Mukherjee, S., Nalam, R. L., et al. (2011) Mendelian genetics of male infertility. Ann. N. Y. Acad. Sci. 1214, E1-E17.
121. Jamsai, D., and, O'Bryan, M. K., (2011) Mouse models in male fertility research. Asian J. Androl. 13, 139-151.
122. Dennler, S., Andre, J., Alexaki, I., Li, A., Magnaldo, T., et al. (2007) Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67, 6981-6986.
123. Charbonney, E., Speight, P., Masszi, A., Nakano, H., and, Kapus, A., (2011) B-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition. Mol. Cell. Biol. 22, 4472-4485.
124. Fujii, M., Toyoda, T., Nakanishi, H., Yatabe, Y., Sato, A., et al. (2012) TGFb synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J. Exp. Med. 209, 479-494.
125. Cooper, T. G., Noonan, E., von Eckardstein, S., Auger, J., Baker, H. W. G., et al. (2010) World Health Organization reference values for human semen characteristics. Hum. Reprod. Update 163, 231-245.