This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morita, Y. Articles by Tilly, J. L. Search for Related Content PubMed PubMed Citation Articles by Morita, Y. Articles by Tilly, J. L.

Targeted Expression of Bcl-2 in Mouse Oocytes Inhibits Ovarian Follicle Atresia and Prevents Spontaneous and Chemotherapy-Induced Oocyte Apoptosis In Vitro

Vincent Center for Reproductive Biology Department of Obstetrics and Gynecology Massachusetts General Hospital/Harvard Medical School Boston, Massachusetts 02114

Members of the Bcl-2 family serve as central checkpoints for cell death regulation, and overexpression of Bcl-2 is known to inhibit apoptosis in many cell types. To determine whether targeted expression of Bcl-2 could be used to protect female germ cells from apoptosis, we generated transgenic mice expressing fully functional human Bcl-2 protein only in oocytes. Transgenic mice were produced using a previously characterized 480-bp fragment of the mouse zona pellucida protein-3 (ZP3) gene 5'-flanking region to direct oocyte-specific expression of a human bcl-2 complementary DNA. Immunohistochemical analyses using a human Bcl-2-specific antibody showed that transgene expression was restricted to growing oocytes and was not observed in the surrounding ovarian somatic cells or in any other nonovarian tissues. Histomorphometric analyses revealed that ovaries collected from transgenic female mice possessed significantly fewer atretic small preantral follicles compared with wild-type sisters, resulting in a larger population of healthy maturing follicles per ovary. However, the number of oocytes ovulated in response to exogenous gonadotropin priming and the number of pups per litter were not significantly different among wild-type vs. transgenic female mice. Nonetheless, oocytes obtained from transgenic mice and cultured in vitro were found to be resistant to spontaneous and anticancer drug-induced apoptosis. We conclude that targeted expression of Bcl-2 only in oocytes can be achieved as a means to convey resistance of the female germ line to naturally occurring and chemotherapy-induced apoptosis.

This article has been cited by other articles:

				M. J Agulleiro, M. Andre, S. Morais, J. Cerda, and P. J Babin High Transcript Level of Fatty Acid-Binding Protein 11 but Not of Very Low-Density Lipoprotein Receptor Is Correlated to Ovarian Follicle Atresia in a Teleost Fish (Solea senegalensis) Biol Reprod, September 1, 2007; 77(3): 504 - 516. [Abstract] [Full Text] [PDF]

				Z. Blumenfeld How to Preserve Fertility in Young Women Exposed to Chemotherapy? The Role of GnRH Agonist Cotreatment in Addition to Cryopreservation of Embrya, Oocytes, or Ovaries Oncologist, September 1, 2007; 12(9): 1044 - 1054. [Abstract] [Full Text] [PDF]

				J. L. Kipp, S. M. Kilen, S. Bristol-Gould, T. K. Woodruff, and K. E. Mayo Neonatal Exposure to Estrogens Suppresses Activin Expression and Signaling in the Mouse Ovary Endocrinology, May 1, 2007; 148(5): 1968 - 1976. [Abstract] [Full Text] [PDF]

				J. A. Visser, A. L. L. Durlinger, I. J. J. Peters, E. R. van den Heuvel, U. M. Rose, P. Kramer, F. H. de Jong, and A. P. N. Themmen Increased Oocyte Degeneration and Follicular Atresia during the Estrous Cycle in Anti-Mullerian Hormone Null Mice Endocrinology, May 1, 2007; 148(5): 2301 - 2308. [Abstract] [Full Text] [PDF]

				C. R Greenfeld, J. K Babus, P. A Furth, S. Marion, P. B Hoyer, and J. A Flaws BAX is involved in regulating follicular growth, but is dispensable for follicle atresia in adult mouse ovaries Reproduction, January 1, 2007; 133(1): 107 - 116. [Abstract] [Full Text] [PDF]

				K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws Ovarian follicle development and transgenic mouse models Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555. [Abstract] [Full Text] [PDF]

				J B Kerr, R Duckett, M Myers, K L Britt, T Mladenovska, and J K Findlay Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply Reproduction, July 1, 2006; 132(1): 95 - 109. [Abstract] [Full Text] [PDF]

				M Shozu, N Minami, H Yokoyama, M Inoue, H Kurihara, K Matsushima, and K Kuno ADAMTS-1 is involved in normal follicular development, ovulatory process and organization of the medullary vascular network in the ovary J. Mol. Endocrinol., October 1, 2005; 35(2): 343 - 355. [Abstract] [Full Text] [PDF]

				N. Fulton, S. J. Martins da Silva, R. A. L. Bayne, and R. A. Anderson Germ Cell Proliferation and Apoptosis in the Developing Human Ovary J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4664 - 4670. [Abstract] [Full Text] [PDF]

				M. Di Giacomo, M. Barchi, F. Baudat, W. Edelmann, S. Keeney, and M. Jasin Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants PNAS, January 18, 2005; 102(3): 737 - 742. [Abstract] [Full Text] [PDF]

				Z. Roth and P.J. Hansen Involvement of Apoptosis in Disruption of Developmental Competence of Bovine Oocytes by Heat Shock During Maturation Biol Reprod, December 1, 2004; 71(6): 1898 - 1906. [Abstract] [Full Text] [PDF]

				D. Tomic, K. P. Miller, H. A. Kenny, T. K. Woodruff, P. Hoyer, and J. A. Flaws Ovarian Follicle Development Requires Smad3 Mol. Endocrinol., September 1, 2004; 18(9): 2224 - 2240. [Abstract] [Full Text] [PDF]

				S. Di Cosimo, A. Alimonti, G. Ferretti, I. Sperduti, P. Carlini, P. Papaldo, A. Fabi, A. Gelibter, M. Ciccarese, D. Giannarelli, et al. Incidence of chemotherapy-induced amenorrhea depending on the timing of treatment by menstrual cycle phase in women with early breast cancer Ann. Onc., July 1, 2004; 15(7): 1065 - 1071. [Abstract] [Full Text] [PDF]

				C. Borgeest, K. P. Miller, R. Gupta, C. Greenfeld, K. S. Hruska, P. Hoyer, and J. A. Flaws Methoxychlor-Induced Atresia in the Mouse Involves Bcl-2 Family Members, but Not Gonadotropins or Estradiol Biol Reprod, June 1, 2004; 70(6): 1828 - 1835. [Abstract] [Full Text] [PDF]

				K. H. Burns, G. E. Owens, S. C. Ogbonna, J. H. Nilson, and M. M. Matzuk Expression Profiling Analyses of Gonadotropin Responses and Tumor Development in the Absence of Inhibins Endocrinology, October 1, 2003; 144(10): 4492 - 4507. [Abstract] [Full Text] [PDF]

				C. J. Guigon, S. Mazaud, M. G. Forest, S. Brailly-Tabard, N. Coudouel, and S. Magre Unaltered Development of the Initial Follicular Waves and Normal Pubertal Onset in Female Rats after Neonatal Deletion of the Follicular Reserve Endocrinology, August 1, 2003; 144(8): 3651 - 3662. [Abstract] [Full Text] [PDF]

				Y. Takai, J. Canning, G. I. Perez, J. K. Pru, J. J. Schlezinger, D. H. Sherr, R. N. Kolesnick, J. Yuan, R. A. Flavell, S. J. Korsmeyer, et al. Bax, Caspase-2, and Caspase-3 Are Required for Ovarian Follicle Loss Caused by 4-Vinylcyclohexene Diepoxide Exposure of Female Mice in Vivo Endocrinology, January 1, 2003; 144(1): 69 - 74. [Abstract] [Full Text] [PDF]

				P. S. Hartley, R. A. L. Bayne, L. L. L. Robinson, N. Fulton, and R. A. Anderson Developmental Changes in Expression of Myeloid Cell Leukemia-1 in Human Germ Cells during Oogenesis and Early Folliculogenesis J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3417 - 3427. [Abstract] [Full Text] [PDF]

				A. C. Gordo, P. Rodrigues, M. Kurokawa, T. Jellerette, G. E. Exley, C. Warner, and R. Fissore Intracellular Calcium Oscillations Signal Apoptosis Rather than Activation in In Vitro Aged Mouse Eggs Biol Reprod, June 1, 2002; 66(6): 1828 - 1837. [Abstract] [Full Text] [PDF]

				F. Limana, K. Urbanek, S. Chimenti, F. Quaini, A. Leri, J. Kajstura, B. Nadal-Ginard, S. Izumo, and P. Anversa bcl-2 overexpression promotes myocyte proliferation PNAS, April 30, 2002; 99(9): 6257 - 6262. [Abstract] [Full Text] [PDF]

				T. M. Matikainen, T. Moriyama, Y. Morita, G. I. Perez, S. J. Korsmeyer, D. H. Sherr, and J. L. Tilly Ligand Activation of the Aromatic Hydrocarbon Receptor Transcription Factor Drives Bax-Dependent Apoptosis in Developing Fetal Ovarian Germ Cells Endocrinology, February 1, 2002; 143(2): 615 - 620. [Abstract] [Full Text] [PDF]

				T. E. Vaskivuo, M. Anttonen, R. Herva, H. Billig, M. Dorland, E. R. te Velde, F. Stenback, M. Heikinheimo, and J. S. Tapanainen Survival of Human Ovarian Follicles from Fetal to Adult Life: Apoptosis, Apoptosis-Related Proteins, and Transcription Factor GATA-4 J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3421 - 3429. [Abstract] [Full Text] [PDF]

				J. K. Pru and J. L. Tilly Programmed Cell Death in the Ovary: Insights and Future Prospects Using Genetic Technologies Mol. Endocrinol., June 1, 2001; 15(6): 845 - 853. [Abstract] [Full Text] [PDF]

				T. Matikainen, G. I. Perez, T. S. Zheng, T. R. Kluzak, B. R. Rueda, R. A. Flavell, and J. L. Tilly Caspase-3 Gene Knockout Defines Cell Lineage Specificity for Programmed Cell Death Signaling in the Ovary Endocrinology, June 1, 2001; 142(6): 2468 - 2480. [Abstract] [Full Text] [PDF]

				J. A. Flaws, A. N. Hirshfield, J. A. Hewitt, J. K. Babus, and P. A. Furth Effect of Bcl-2 on the Primordial Follicle Endowment in the Mouse Ovary Biol Reprod, April 1, 2001; 64(4): 1153 - 1159. [Abstract] [Full Text]

				A. C. Gordo, H. Wu, C. L. He, and R. A. Fissore Injection of Sperm Cytosolic Factor Into Mouse Metaphase II Oocytes Induces Different Developmental Fates According to the Frequency of [Ca2+]i Oscillations and Oocyte Age Biol Reprod, May 1, 2000; 62(5): 1370 - 1379. [Abstract] [Full Text]