This Article Full Text Full Text (PDF) 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 MacLean, G. Articles by Petkovich, M. Search for Related Content PubMed PubMed Citation Articles by MacLean, G. Articles by Petkovich, M.

Apoptotic Extinction of Germ Cells in Testes of Cyp26b1 Knockout Mice

Departments of Pathology and Molecular Medicine (G.M., M.P., H.L.), and Biochemistry (M.P.), Division of Cancer Biology and Genetics (G.M., H.L., M.P.), Cancer Research Institute (G.M., M.P.), Queen’s University, Kingston, Ontario, Canada K7L 3N6; and Institut de Génétique et de Biologie Moléculaire et Cellulaire (D.M., P.C.), Collège de France, Illkirch 67404, CU de Strasbourg, France

Address all correspondence and requests for reprints to: Dr. Martin Petkovich, Ph.D., Cancer Research Institute, Division of Cancer Biology and Genetics, Botterell Hall, Room 354, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail: petkovic{at}post.queensu.ca.

Cyp26b1 encodes a retinoic acid (RA) metabolizing cytochrome P450 enzyme that is expressed in embryonic tissues undergoing morphogenesis, including the testes. We have generated transgenic mice lacking Cyp26b1 and have observed increased RA levels in embryonic testes. Cyp26b1^–/– germ cells prematurely enter meiosis at embryonic d 13.5 and appear to arrest at pachytene stage. Furthermore, after embryonic d 13.5, a rapid increase in apoptosis is observed in male germ cells derived from Cyp26b1^–/– embryos; germ cells are essentially absent in mutant male neonates. In contrast, testicular somatic cells appear to develop normally in the absence of Cyp26b1. Moreover, ovarian germ and somatic cells appear unaffected by the lack of CYP26B1. We also show that the synthetic retinoid Am580, which is resistant to CYP26 metabolism, induces meiosis of male germ cells in cultured gonads, suggesting that abnormal development of germ cells in the Cyp26b1^–/– testes results from excess RA rather than the absence of CYP26B1-generated metabolites of RA. These results provide evidence that CYP26B1 maintains low levels of RA in the developing testes that blocks entry into meiosis and acts as a survival factor to prevent apoptosis of male germ cells.

This article has been cited by other articles:

				S. M. Nowickyj, J. V. Chithalen, D. Cameron, M. G. Tyshenko, M. Petkovich, G. R. Wyatt, G. Jones, and V. K. Walker Locust retinoid X receptors: 9-Cis-retinoic acid in embryos from a primitive insect PNAS, July 15, 2008; 105(28): 9540 - 9545. [Abstract] [Full Text] [PDF]

				S. Otsuka, A. Konno, Y. Hashimoto, N. Sasaki, D. Endoh, and Y. Kon Oocytes in Newborn MRL Mouse Testes Biol Reprod, July 1, 2008; 79(1): 9 - 16. [Abstract] [Full Text] [PDF]

				A. Suzuki and Y. Saga Nanos2 suppresses meiosis and promotes male germ cell differentiation Genes & Dev., February 15, 2008; 22(4): 430 - 435. [Abstract] [Full Text] [PDF]

				W. S. Blaner and C. L. Mendelsohn Retinoid Inactivation: Survival Factor for Male Germ Cells Endocrinology, October 1, 2007; 148(10): 4557 - 4559. [Full Text] [PDF]

				J. Bowles and P. Koopman Retinoic acid, meiosis and germ cell fate in mammals Development, October 1, 2007; 134(19): 3401 - 3411. [Abstract] [Full Text] [PDF]