This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zindy, F.
Right arrow Articles by Roussel, M. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zindy, F.
Right arrow Articles by Roussel, M. F.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2001, p. 3244-3255, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3244-3255.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Control of Spermatogenesis in Mice by the Cyclin D-Dependent Kinase Inhibitors p18Ink4c and p19Ink4d

Frederique Zindy,1 Willem den Besten,1 Bo Chen,2 Jerold E. Rehg,3 Esther Latres,4 Mariano Barbacid,5 Jeffrey W. Pollard,2 Charles J. Sherr,1,6 Paula E. Cohen,2,dagger and Martine F. Roussel1,*

Departments of Tumor Cell Biology1 and Pathology3 and Howard Hughes Medical Institute,6 St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 104612; Department of Pathology, New York University School of Medicine, New York, New York 100164; and Centro Nacional de Investigaciones Oncologicas Carlos III, Majadahonda, 28220 Madrid, Spain5

Received 14 November 2000/Returned for modification 14 December 2000/Accepted 13 February 2001

Male mice lacking both the Ink4c and Ink4d genes, which encode two inhibitors of D-type cyclin-dependent kinases (Cdks), are infertile, whereas female fecundity is unaffected. Both p18Ink4c and p19Ink4d are expressed in the seminiferous tubules of postnatal wild-type mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Their combined loss is associated with the delayed exit of spermatogonia from the mitotic cell cycle, leading to the retarded appearance of meiotic cells that do not properly differentiate and instead undergo apoptosis at an increased frequency. As a result, mice lacking both Ink4c and Ink4d produce few mature sperm, and the residual spermatozoa have reduced motility and decreased viability. Whether or not Ink4d is present, animals lacking Ink4c develop hyperplasia of interstitial testicular Leydig cells, which produce reduced levels of testosterone. The anterior pituitary of fertile mice lacking Ink4c or infertile mice doubly deficient for Ink4c and Ink4d produces normal levels of luteinizing hormone (LH). Therefore, the failure of Leydig cells to produce testosterone is not secondary to defects in LH production, and reduced testosterone levels do not account for infertility in the doubly deficient strain. By contrast, Ink4d-null or double-null mice produce elevated levels of follicle-stimulating hormone (FSH). Because Ink4d-null mice are fertile, increased FSH production by the anterior pituitary is also unlikely to contribute to the sterility observed in Ink4c/Ink4d double-null males. Our data indicate that p18Ink4c and p19Ink4d are essential for male fertility. These two Cdk inhibitors collaborate in regulating spermatogenesis, helping to ensure mitotic exit and the normal meiotic maturation of spermatocytes.

* Corresponding author. Mailing address: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3481. Fax: (901) 495-2381. E-mail: martine.roussel{at}stjude.org.

dagger Present address: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461.

Molecular and Cellular Biology, May 2001, p. 3244-3255, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3244-3255.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Gromley, A., Churchman, M. L., Zindy, F., Sherr, C. J. (2009). Transient expression of the Arf tumor suppressor during male germ cell and eye development in Arf-Cre reporter mice. Proc. Natl. Acad. Sci. USA 106: 6285-6290 [Abstract] [Full Text]  
  • Lue, Y., Wang, C., Cui, Y., Wang, X., Sha, J., Zhou, Z., Xu, J., Wang, C., Sinha Hikim, A. P., Swerdloff, R. S. (2009). Levonorgestrel Enhances Spermatogenesis Suppression by Testosterone with Greater Alteration in Testicular Gene Expression in Men. Biol. Reprod. 80: 484-492 [Abstract] [Full Text]  
  • Quereda, V., Malumbres, M. (2009). Cell cycle control of pituitary development and disease. J Mol Endocrinol 42: 75-86 [Abstract] [Full Text]  
  • Gilles, L., Guieze, R., Bluteau, D., Cordette-Lagarde, V., Lacout, C., Favier, R., Larbret, F., Debili, N., Vainchenker, W., Raslova, H. (2008). P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1. Blood 111: 4081-4091 [Abstract] [Full Text]  
  • Ramsey, M. R., Krishnamurthy, J., Pei, X.-H., Torrice, C., Lin, W., Carrasco, D. R., Ligon, K. L., Xiong, Y., Sharpless, N. E. (2007). Expression of p16Ink4a Compensates for p18Ink4c Loss in Cyclin-Dependent Kinase 4/6-Dependent Tumors and Tissues. Cancer Res. 67: 4732-4741 [Abstract] [Full Text]  
  • Cohen, P. E., Pollack, S. E., Pollard, J. W. (2006). Genetic Analysis of Chromosome Pairing, Recombination, and Cell Cycle Control during First Meiotic Prophase in Mammals. Endocr. Rev. 27: 398-426 [Abstract] [Full Text]  
  • Gomez, O., Romero, A., Terrado, J., Mesonero, J. E (2006). Differential expression of glucose transporter GLUT8 during mouse spermatogenesis. Reproduction 131: 63-70 [Abstract] [Full Text]  
  • Morelli, M. A, Cohen, P. E (2005). Not all germ cells are created equal: Aspects of sexual dimorphism in mammalian meiosis. Reproduction 130: 761-781 [Abstract] [Full Text]  
  • Chen, B., Pan, H., Zhu, L., Deng, Y., Pollard, J. W. (2005). Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase->AKT->GSK-3{beta}->Cyclin D1->pRB Pathway to Block Uterine Epithelial Cell Proliferation. Mol. Endocrinol. 19: 1978-1990 [Abstract] [Full Text]  
  • Zhang, H., McElrath, T., Tong, W., Pollard, J. W (2005). The molecular basis of tamoxifen induction of mouse uterine epithelial cell proliferation. J Endocrinol 184: 129-140 [Abstract] [Full Text]  
  • Zindy, F., Williams, R. T., Baudino, T. A., Rehg, J. E., Skapek, S. X., Cleveland, J. L., Roussel, M. F., Sherr, C. J. (2003). Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc. Natl. Acad. Sci. USA 100: 15930-15935 [Abstract] [Full Text]  
  • Hewitt, S. C., Deroo, B. J., Hansen, K., Collins, J., Grissom, S., Afshari, C. A., Korach, K. S. (2003). Estrogen Receptor-Dependent Genomic Responses in the Uterus Mirror the Biphasic Physiological Response to Estrogen. Mol. Endocrinol. 17: 2070-2083 [Abstract] [Full Text]  
  • Zindy, F., Nilsson, L. M., Nguyen, L., Meunier, C., Smeyne, R. J., Rehg, J. E., Eberhart, C., Sherr, C. J., Roussel, M. F. (2003). Hemangiosarcomas, Medulloblastomas, and Other Tumors in Ink4c/p53-null Mice. Cancer Res. 63: 5420-5427 [Abstract] [Full Text]  
  • Lee, Y., Miller, H. L., Jensen, P., Hernan, R., Connelly, M., Wetmore, C., Zindy, F., Roussel, M. F., Curran, T., Gilbertson, R. J., McKinnon, P. J. (2003). A Molecular Fingerprint for Medulloblastoma. Cancer Res. 63: 5428-5437 [Abstract] [Full Text]  
  • Jirawatnotai, S., Moons, D. S., Stocco, C. O., Franks, R., Hales, D. B., Gibori, G., Kiyokawa, H. (2003). The Cyclin-dependent Kinase Inhibitors p27Kip1 and p21Cip1 Cooperate to Restrict Proliferative Life Span in Differentiating Ovarian Cells. J. Biol. Chem. 278: 17021-17027 [Abstract] [Full Text]  
  • Cunto, F. D., Imarisio, S., Camera, P., Boitani, C., Altruda, F., Silengo, L. (2003). Essential role of citron kinase in cytokinesis of spermatogenic precursors. J. Cell Sci. 115: 4819-4826 [Abstract] [Full Text]  
  • Liou, Y.-C., Ryo, A., Huang, H.-K., Lu, P.-J., Bronson, R., Fujimori, F., Uchida, T., Hunter, T., Lu, K. P. (2002). Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc. Natl. Acad. Sci. USA 10.1073/pnas.032404099v1 [Abstract] [Full Text]  
  • Wang, Z., Yu, R., Melmed, S. (2001). Mice Lacking Pituitary Tumor Transforming Gene Show Testicular and Splenic Hypoplasia, Thymic Hyperplasia, Thrombocytopenia, Aberrant Cell Cycle Progression, and Premature Centromere Division. Mol. Endocrinol. 15: 1870-1879 [Abstract] [Full Text]  
  • Liou, Y.-C., Ryo, A., Huang, H.-K., Lu, P.-J., Bronson, R., Fujimori, F., Uchida, T., Hunter, T., Lu, K. P. (2002). Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc. Natl. Acad. Sci. USA 99: 1335-1340 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»