title: CYP26B1 promotes male germ cell differentiation by suppressing STRA8-dependent meiotic and STRA8-independent mitotic pathways.
abstract: Germ cell sex is defined by factors derived from somatic cells. CYP26B1 is known to be a male sex-promoting factor that inactivates retinoic acid (RA) in somatic cells. In CYP26B1-null XY gonads, germ cells are exposed to a higher level of RA than in normal XY gonads and this activates Stra8 to induce meiosis while male-specific gene expression is suppressed. However, it is unknown whether meiotic entry by an elevated level of RA is responsible for the suppression of male-type gene expression. To address this question, we have generated Cyp26b1/Stra8 double knockout (dKO) embryos. We successfully suppressed the induction of meiosis in CYP26B1-null XY germ cells by removing the Stra8 gene. Concomitantly, we found that the male genetic program represented by the expression of NANOS2 and DNMT3L was totally rescued in about half of dKO germ cells, indicating that meiotic entry causes the suppression of male differentiation. However, half of the germ cells still failed to enter the appropriate male pathway in the dKO condition. Using microarray analyses together with immunohistochemistry, we found that KIT expression was accompanied by mitotic activation, but was canceled by inhibition of the RA signaling pathway. Taken together, we conclude that inhibition of RA is one of the essential factors to promote male germ cell differentiation, and that CYP26B1 suppresses two distinct genetic programs induced by RA: a Stra8-dependent meiotic pathway, and a Stra8-independent mitotic pathway.
authors.affiliation: Division of Mammalian Development, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan. Electronic address: ysaga@nig.ac.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Saba
authors.affiliation: Division of Mammalian Development, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan; Department of Genetics, SOKENDAI, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Division of Mammalian Development, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan; Department of Genetics, SOKENDAI, 1111 Yata, Mishima, Shizuoka 411-8540, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005854:Germ Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008540:Meiosis / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C477341:Nanos2 protein, mouse; D016601:RNA-Binding Proteins; C102019:Stra8 protein, mouse; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D019009:Proto-Oncogene Proteins c-kit
keywords: Cyp26b1; Germ cell; Kit; Meiosis; Mitosis; Retinoic acid; Stra8