Apoptotic Signaling in Male Germ Cells

Amiya P. Sinha Hikim; Yue Jia; Yan-He Lue; Christina Wang; Ronald S. Swerdloff

doi:10.1017/CBO9780511976094.025

25 - Apoptotic Signaling in Male Germ Cells

from Part II - Cell Death in Tissues and Organs

Published online by Cambridge University Press: 07 September 2011

Douglas R. Green

Amiya P. Sinha Hikim ,

Yue Jia ,

Yan-He Lue ,

Christina Wang and

Ronald S. Swerdloff

Edited by

John C. Reed

Show author details

Douglas R. Green: Affiliation:
St. Jude Children's Research Hospital, Memphis, Tennessee
Amiya P. Sinha Hikim: Affiliation:
David Geffen School of Medicine at UCLA
Yue Jia: Affiliation:
David Geffen School of Medicine at UCLA
Yan-He Lue: Affiliation:
David Geffen School of Medicine at UCLA
Christina Wang: Affiliation:
David Geffen School of Medicine at UCLA
Ronald S. Swerdloff: Affiliation:
David Geffen School of Medicine at UCLA
John C. Reed: Affiliation:
Sanford-Burnham Medical Research Institute, La Jolla, California

Book contents

Get access

Summary

Abstract

Programmed germ cell death (apoptosis) is conspicuous during normal spermatogenesis and serves as a quality control system for the production of normal sperm. Deregulation of germ cell death is associated with defective spermatogenesis and impaired fertility. Mitochondria-dependent intrinsic pathway signaling constitutes a critical component of apoptotic signaling in male germ cells across species. However, the regulation of germ cell apoptosis may vary depending on the nature of the apoptotic stimulus and can be triggered by more than one pathway. Activation of p38 mitogen-activated protein kinase (MAPK) and induction of inducible nitric oxide synthase are critical for activation of the intrinsic pathway signaling in male germ cells. In addition, there is increasing evidence that caspase-2 is an upstream activator of the p38 MAPK and nitric oxide–mediated intrinsic pathway signaling. This chapter focuses on the recent progress in our understanding of the regulation of germ cell apoptosis in the testis.

Type: Chapter
Information: Apoptosis
Physiology and Pathology
, pp. 283 - 294

DOI: https://doi.org/10.1017/CBO9780511976094.025 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Baum, JS, St. George, JP, McCall, GK (2005) Programmed cell death in the germ line. Semin Cell Dev Biol 16: 245–59.

Boussouar, F, Benahmed, M (2004) Lactate and energy metabolism in male germ cells. Trends Endo Metab 15: 345–50.

Bu, SZ, Huang, Q, Jiang, YM, Min, HB, Hou, Y, Guo, ZY, Wei, JF, Wang, GW, Ni, X, Zheng, SS (2006) p38 mitogen-activated protein kinase is required for counteraction of 2-methoxyestradiol to estradiol-stimulated cell proliferation and induction of apoptosis in ovarian carcinoma cells via phosphorylation of Bcl-2. Apoptosis 11: 413–25.

Castanares, M, Vera, Y, Erkkila, K, Kyttanen, S, Lue, Y, Dunkel, L, Wang, C, Swerdloff, RS, Sinha Hikim, AP (2005) Minocycline up-regulates BCL-2 levels in mitochondria and attenuates male germ cell apoptosis. Biochem Biophys Res Commun 337: 663–9.

Castellanos, J. (2007) Characterization of signaling pathways that culminate in activation of the intrinsic pathway signaling for male germ cell death triggered by hormone deprivation or by testicular hyperthermia. Master of Science Thesis. Dominguez Hills, CA: California State University at Dominguez Hills.

Cecconi, F, Alvarez-Bolado, G, Meyer, BI, Roth, KA, Gruss, P (1998) Apaf-1 (CED- 4 homolog) regulates programmed cell death in mammalian development. Cell 94: 727–37.

Danial, NN, Korsmeyer, SJ (2004) Cell death: critical control points. Cell 116: 205–19.

Dix, DJ, Allen, JW, Collins, BW, Mori, C, Nakamura, N, Poorman-Allen, P, Goulding, EH, Eddy, EM (1996) Targeted gene disruption of Hsp 70–2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc Natl Acad Sci USA 93: 3264–8.

Dunkel, L, Taskinen, S, Hovatta, O, Tilly, JL, Wikstrom, S (1997) Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. J Clin Invest 100: 2341–6.

Fan, M, Goodwin, M, Vu, T, Brantley-Finley, C, Gaarde, WA, Chambers, TC (2000) Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. J Biol Chem 29: 29980–5.

Halder, S, Basu, A, Croce, CM (1998) Serine-70 is one of the critical sites for drug-induced Bcl-2 phosphorylation in cancer cells. Cancer Res 58: 1609–15.

Honarpour, N, Du, C, Richardson, JA, Hammer, RE, Wang, X, Hertz, J (2000) Adult Apaf-1-deficient mice exhibit male infertility. Dev Biol 248–58.

Hsu, SY, Lai, RJ-M, Finegold, M, Hsueh, AJW (1996) Targeted overexpression of Bcl-2 in ovaries of transgenic mice leads to decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis. Endocrinology 137: 4837–43.

Jia, Y, Sinha Hikim, AP, Swerdloff, RS, Lue, YH, Vera, Y, Zhang, X-S, Hu, Z-Y, Li, Y-C, Liu, Y-X, Wang, C (2007) Signaling pathways for germ cell death in adult Cynomolgus monkeys (Macaca fascicularis) induced by mild testicular hyperthermia and exogenous testosterone treatment. Biol Reprod 77: 83–92.

Johnson, C, Jia, Y, Wang, C, Lue, Y, Swerdloff, RS, Zhang, X-S, Hu, Z-Y, Li, Y-C, Liu, Y-X, Sinha Hikim, AP (2008) Role of caspase 2 in apoptotic signaling of primate and murine germ cells. Biol Reprod 79: 806–14.

Knudson, CM, Tung, KSK, Tourtellotte, WG, Brown, GAJ, Korsmeyer, SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270:96–9.

Lee, WN (2006) Characterizing phenotype with tracer based metabolomics. Metabolomics 2: 31–9.

Liu, PY, Swerdloff, RS, Christenson, PD, Handelsman, DJ, Wang, C, and the Hormonal Male Contraception Summit group (2006) Rate, extent, and modifiers of spermatogenic recovery after male contraception: an integrated analysis. Lancet 367: 1412–20.

Lue, YH, Sinha Hikim, AP, Swerdloff, RS, Im, P, Taing, KS, Bui, T, Leung, A, Wang, C (1999) Single exposure to heat induces stage-specific germ cell apoptosis in rats: role of intratesticular testosterone (T) on stage specificity. Endocrinology 140:1709–17.

Lue, YH, Sinha Hikim, AP, Wang, C, Im, M, Leung, A, Swerdloff, RS (2000) Testicular heat exposure enhances the suppression of spermatogenesis by testosterone in rats: the “two-hit” approach to male contraceptive development. Endocrinology 141:1414–24.

Lue, YH, Wang, C, Liu, Y-X, Zhang, XS, Sinha Hikim, AP, Zhang, X-S, Ng, CM, Hu, Z-Y, Li, Y-C, Leung, A, Swerdloff, RS (2006) Transient testicular warming enhances the suppressive effect of testosterone on spermatogenesis in adult cynomolgus monkeys (Macaca fascicularis). J Clin Endocrinol Metab 91: 539–45.

Lysiak, JL, Zheng, S, Woodson, R, Turner, TT (2007) Caspase-9-dependent pathway to murine germ cell apoptosis: mediation by oxidative stress, BAX, and caspase 2. Cell Tissue Res 328: 411–9.

Matzuk, MM, Lamb, DJ (2002) Genetic dissection of mammalian fertility pathways. Nat Cell Biol Suppl 4: s41–9.

McKee, CM, Ye, Y, Richburg, JH (2006) Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment. Apoptosis 11: 2237–50.

Nagata, S, Golstein, P (1995) The Fas death factor. Science 267: 1449–55.

Nair, R, Shaha, C (2003) Diethylstilbestrol induces rat spermatogenic cell apoptosis in vitro through increased expression of spermatogenic cell Fas/FasL system. J Biol Chem 278: 6470–81.

Pentikaainen, V, Dunkel, L, Erkkila, K (2003) Male germ cell apoptosis. Endocr Dev 5: 56–80.

Perez, GI, Robles, R, Knudson, CM, Flaws, JA, Korsmeyer, SJ, Tilly, JL (1999) Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet 21: 200–3.

Print, CG, Loveland, KL, Gibson, L, Meehan, T, Stylianou, A, Wreford, N, DeKretser, D, Metcalf, D, Kontgen, F, Adams, JM, Cory, S (1998) Apoptosis regulator Bcl-w is essential spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci U S A 95: 12424–31.

Rajah, R, Lee, K-W, Cohen, P (2002) Insulin-like growth factor binding protein 3 mediates tumor necrosis factor-α-induced apoptosis: role of Bcl-2 phosphorylation. Cell Growth Differ 13: 163–171.

Rao, MK, Pham, J, Imam, S, MacLean, J, Murali, D, Furuta, Y, Sinha Hikim, AP, Wilkinson, MF (2006) Tissue-specific RNAi reveals that WT1 expression in nurse cells controls germ-cell survival and spermatogenesis. Genes Dev 20: 147–52.

Ross, AJ, Waymire, KG, Moss, JE, Parlow, AF, Skinner, MK, Russell, LD, MacGregor, GR (1998) Testicular degeneration in Bclw-deficient mice. Nat Genet 18: 251–6.

Roest, HP, van Klaveren, J, de Wit, J, van Grup, CG, Koken, MH, Vermey, M, van Roijen, JH, Hoogerbrugge, JW, Vreeburg, JT, Baarends, WM, Bootsma, D, Grootegoed, JA, Hoeijmakers, JH (1996) Inactivation of HR6B ubiquitin-conjugating DNA repair enzyme in mice causes male sterility associated with chromatin modification. Cell 86: 799–810.

Russell, LD, Ettlin, RA, Sinha Hikim, AP, Clegg, ED (1990) Histological and Histopathological Evaluation of the Testis. Clearwater, FL: Cache River Press.

Shaha, C (2007) Modulators of spermatogenic cell survival. Soc Reprod Fertil Suppl 63: 173–86.

Shimada, K, Nakamura, M, Ishida, E, Kishi, M, Konishi, N (2003) Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis. Carcinogenesis 24: 1067–75.

Sinha Hikim, AP, Wang, C, Leung, A, Swerdloff, RS (1995) Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin-releasing hormone antagonist treatment. Endocrinology 136: 2770–5.

Sinha Hikim, AP, Rajavashisth, TB, Sinha Hikim, I, Lue, YHBonavera, JJ, Leung, A, Wang, C, Swerdloff, RS (1997) Quantitative contribution of apoptosis to the temporal and stage-specific loss of germ cells in the adult rat after gonadotropin deprivation. Biol Reprod 57:1193–201.

Sinha Hikim, AP, Lue, YH, Wang, C, Swerdloff, RS (1999) Spermatogenesis and germ cell death. In Wang, C (ed): Male Reproductive Function. Boston, MA: Kluwer Academic Publishers, pp. 19–39.

Sinha Hikim, AP and Swerdloff, RS (1999) Hormonal and genetic control of germ cell apoptosis in the testis. Rev Reprod 4: 38–47.

Sinha Hikim, AP, Lue, Y, Diaz Romero, M, Yen, PH, Wang, C, Swerdloff, RS (2003a) Deciphering the pathways of germ cell apoptosis in the testis. J Steroid Mol Biol 85: 175–82.

Sinha Hikim, AP, Lue, Y, Yamamoto, CM, Vera, Y, Rodriguez, S, Yen, PH, Soeng, K, Wang, C, Swerdloff, RS (2003b) Key apoptotic pathways for heat-induced programmed germ cell death in the testis. Endocrinology 144: 3159–66.

Sinha Hikim, AP, Swerdloff, RS, Wang, C (2005). The testis. In Melmed, S and Conn, M (eds): Endocrinology-Basic and Clinical Principles. Totowa, NJ: Humana Press, pp 405–18.

Sinha Hikim, AP, Vera, Y, Elhag, RI, Lue, Y, Cui, Y-G, Pope, V, Leung, A, Atienza, V, Wang, C, Swerdloff, RS (2005) Mouse model of male germ cell apoptosis in response to a lack of hormonal stimulation. Indian J Exp Biol 43: 1048–57.

Tanaka, SS, Toyooka, Y, Akasu, R, Katoh-Fukui, Y, Nakahara, Y, Suzuki, R, Yokoyama, M, Noce, T (2000) The mouse homolog of Drosophila Vasa is required for the development of male germ cells. Genes Dev 14: 841–53.

Teng, YD, Choi, H, Onario, RC, Zhu, S, Desilets, FC, Lan, S, Woodard, EJ, Snyder, EY, Eichler, ME, Friedlander, RM (2004) Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci USA 101: 3071–6.

Theas, MS, Rival, C, Jarazo Dietrich, S, Guazzone, VA, Lustig, L (2006) Death receptor and mitochondrial pathways are involved in germ cell apoptosis in an experimental model of autoimmune orchitis. Hum Reprod 21: 1734–42.

Tilly, JL (2001) Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol 2: 838–48.

Vera, Y, Diaz-Romero, M, Rodriguez, S, Lue, Y, Wang, C, Swerdloff, RS, Sinha Hikim, AP (2004) Mitochondria-dependent apoptotic pathway is involved in heat-induced male germ cell death: lessons from mutant mice. Biol Reprod 70: 1534–40.

Vera, Y, Rodriguez, A, Castanares, M, Lue, Y, Atienza, V, Wang, C, Swerdloff, RS, Sinha Hikim, AP (2005) Functional role of caspases in heat-induced testicular germ cell apoptosis. Biol Reprod 72: 516–22.

Vera, Y, Erkkila, K, Wang, C, Nunez, C, Kyttanen, S, Lue, Y, Dunkel, L, Swerdloff, RS, Sinha Hikim, AP (2006) Involvement of p38 mitogen-activated protein kinase and inducible nitric oxide synthase in apoptotic signaling of murine and human male germ cells after hormone deprivation. Mol Endocrinol 20: 1597–609.

Wang, C, Swerdloff, RS (2004) Male hormonal contraception. Am J Obstet Gynecol 190: S60–68.

Wang, C, Cui, YG, Wang, XH, Jia, Y, Sinha Hikim, A, Lue, YH, Tong, JS, Qian, LX, Sha, JH, Zhou, ZM, Hull, L, Leung, A, Swerdloff, RS (2007) Transient scrotal hyperthermia and levonorgestrel enhance testosterone induced spermatogenesis suppression in men through increased germ cell apoptosis. J Clin Endocrinol Metab 92: 3292–04.

Wei, X, Zhao, L, Liu, J, Dodel, RC, Farlow, MR, Du, Y (2005) Minocycline prevents gentamicin-induced cytotoxicity by inhibiting p38 MAP kinase phosphorylation and caspase 3 activation. Neuroscience 131:513–21.

Yamamoto, CM, Sinha Hikim, AP, Lue, YH, Portugal, AM, Guo, TB, Hsu, SY, Salameh, WA, Wang, C, Hsueh, AJW, Swerdloff, RS (2001) Impairment of spermatogenesis in transgenic mice with selective over expression of Bel-2 in the somatic cells of the testis. J Androl 22:981–91.

Yoshida, H, Kong, Y-Y, Yoshida, R, Elia, AJ, Hakem, A, Hakem, R, Penninger, JM, Mak, TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94: 739–50.

Youle, RJ, Srasser, A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47–59.

Zhang, D, Penttila, T-L, Morris, PL, Teichmann, M, Roeder, RG (2001) Spermiogenesis deficiency in mice lacking the Trf2 gene. Science 292: 1153–55.

Zhang, X-S, Zhang, Z-H, Jin, X, Wei, P, Hu, X-Q, Chen, M, Lu, C-L, Lue, Y, Hu, Z-Y, Sinha Hikim, AP, Swerdloff, RS, Wang, C, Liu, Y-X (2006) Dedifferentiation of adult monkey Sertoli cells through activation of ERK1/2 kinase induced by heat treatment. Endocrinology 147: 1237–45.

Zheng, S, Turner, TT, Lysiak, JL (2006) Caspase 2 activity contributes to the initial wave of germ cell apoptosis during the first round of spermatogenesis. Biol Reprod 74: 1026–33.

Zhu, S, Stavrovskaya, IG, Drozda, M, Kim, BYS, Ona, V, Li, M, Sarang, S, Liu, AS, Hartely, DM, Wu, DC, Gullans, S, Ferrante, RJ, Przedborski, S, Kristal, BS, Friedlander, RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417: 74–8.

Book contents

25 - Apoptotic Signaling in Male Germ Cells

Summary

Access options

References

Save book to Kindle

Save book to Dropbox

Save book to Google Drive