MacLean Glenn, Li Hui, Metzger Daniel, Chambon Pierre, Petkovich Martin
Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Endocrinology. 2007 Oct;148(10):4560-7. doi: 10.1210/en.2007-0492. Epub 2007 Jun 21.
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.
Cyp26b1编码一种视黄酸（RA）代谢细胞色素P450酶，该酶在包括睾丸在内的正在进行形态发生的胚胎组织中表达。我们已培育出缺乏Cyp26b1的转基因小鼠，并观察到胚胎睾丸中RA水平升高。Cyp26b1（-/-）生殖细胞在胚胎第13.5天过早进入减数分裂，并似乎停滞在粗线期。此外，在胚胎第13.5天后，观察到源自Cyp26b1（-/-）胚胎的雄性生殖细胞凋亡迅速增加；突变雄性新生儿中基本没有生殖细胞。相比之下，在缺乏Cyp26b1的情况下，睾丸体细胞似乎发育正常。此外，卵巢生殖细胞和体细胞似乎不受CYP26B1缺乏的影响。我们还表明，对CYP26代谢具有抗性的合成视黄酸Am580可诱导培养性腺中雄性生殖细胞的减数分裂，这表明Cyp26b1（-/-）睾丸中生殖细胞的异常发育是由过量的RA而非RA缺乏CYP26B1产生的代谢产物所致。这些结果提供了证据，表明CYP26B1在发育中的睾丸中维持低水平的RA，这可阻止进入减数分裂，并作为一种存活因子防止雄性生殖细胞凋亡。
