NCBI Summary:
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids and other lipids. The enzyme encoded by this gene is involved in the specific inactivation of all-trans-retinoic acid to hydroxylated forms, such as 4-oxo-, 4-OH-, and 18-OH-all-trans-retinoic acid.
Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Naillat F et al. Germ cells are the foundation of an individual, since they generate the gametes and provide the unique genome established through meiosis. The sex-specific fate of the germ line in mammals is thought to be controlled by somatic signals, which are still poorly characterized. We demonstrate here that somatic Wnt signalling is crucial for the control of female germ line development. Wnt-4 maintains germ cell cysts, early follicular gene expression, and provides a female pattern of E-cadherin and ss-catenin expression within the germ cells. In addition, we find that Stra8 expression is down regulated and the Cyp26b1 gene is expressed ectopically in the partially masculinised Wnt-4-deficient ovary. Wnt-4 may control meiosis via these proteins since the Cyp26b1 enzyme is known to degrade retinoic acid and inhibit meiosis in the male embryo, and Stra8 induces meiosis in the female through retinoic acid. Reintroduction of a Wnt-4 signal to the partially masculinised embryonic ovary in fact rescues the female property to a certain degree, as seen by inhibition of Cyp26b1 and induction of Irx3 gene expression. Wnt-4 deficiency allows only 20% of the germ cells to initiate meiosis in the ovary, while meiosis is inhibited completely in the Wnt-4/Wnt-5a double mutant. These findings indicate a critical role for Wnt signalling in meiosis. Thus the Wnt signals are important somatic cell signals that coordinate presumptive female follicle development.
Evidence that injection of vitamin A before mating may improve embryo survival in gilts fed normal or high-energy diets. Whaley SL et al. The hypothesis was that administration of vitamin A before ovulation would improve embryo survival in gilts fed a high-energy diet intentionally to reduce embryo survival. Forty crossbred ([Landrace x Large White] x [Duroc x Hampshire]) gilts were fed control (5.5 Mcal ME/d) or high-energy (11.0 Mcal ME/d) diets from 7 d after second estrus until 11 to 12 d after third estrus. Gilts in each dietary group received (i.m.) corn oil or retinyl palmitate (1 x 10(6) IU, vitamin A) on d 15 after second estrus and were mated at third estrus. Blood for determination of progesterone and estradiol was collected twice daily. The uterus and ovaries were removed on d 11 or 12 after third estrus for assessment of number of CL, and number, size and aromatase activity of embryos. Neither diet nor vitamin treatment affected number of CL. The high-energy diet exerted a negative effect on number of embryos (P = .09) and embryo survival (P = .07), whereas vitamin A exerted a positive effect on number of embryos (P = .07) and embryo survival (P = .08). The high-energy diet increased variation in embryo diameter, whereas vitamin A reduced variation in diameter and increased average diameter. Neither diet nor vitamin treatment influenced aromatase activity of embryos. Diet and vitamin treatment interacted with day to influence serum progesterone, but not estradiol. Injecting vitamin A before estrus restored embryo survival to normal levels in gilts fed high-energy diets, and this may be attributable to decreased variation in size of embryos.
Expression regulated by
Growth Factors/ cytokines
Comment
Gene Expression Profiling Reveals Cyp26b1 to Be an Activin Regulated Gene Involved in Ovarian Granulosa Cell Proliferation. Kipp JL et al. Activin, a member of the TGF-?superfamily, is an important modulator of FSH synthesis and secretion and is involved in reproductive dysfunctions and cancers. It also regulates ovarian follicle development. To understand the mechanisms and pathways by which activin regulates follicle function, we performed a microarray study and identified 240 activin regulated genes in mouse granulosa cells. The gene most strongly inhibited by activin was Cyp26b1, which encodes a P450 cytochrome enzyme that degrades retinoic acid (RA). Cyp26b1 has been shown to play an important role in male germ cell meiosis, but its expression is largely lost in the ovary around embryonic d 12.5. This study demonstrated that Cyp26b1 mRNA was expressed in granulosa cells of follicles at all postnatal developmental stages. A striking inverse spatial and temporal correlation between Cyp26b1 and activin-? mRNA expression was observed. Cyp26b1 expression was also elevated in a transgenic mouse model that has decreased activin expression. The Cyp26 inhibitor R115866 stimulated the proliferation of primary cultured mouse granulosa cells, and a similar effect was observed with RA and activin. A pan-RA receptor inhibitor, AGN194310, abolished the stimulatory effect of either RA or activin on granulosa cell proliferation, indicating an involvement of RA receptor-mediated signaling. Overall, this study provides new insights into the mechanisms of activin action in the ovary. We conclude that Cyp26b1 is expressed in the postnatal mouse ovary, regulated by activin, and involved in the control of granulosa cell proliferation.
Ovarian localization
Primordial Germ Cell, Granulosa
Comment
Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Koubova J et al. . In mammals, meiosis is initiated at different time points in males and females, but the mechanism underlying this difference is unknown. Female germ cells begin meiosis during embryogenesis. In males, embryonic germ cells undergo G0/G1 mitotic cell cycle arrest, and meiosis begins after birth. In mice, the Stimulated by Retinoic Acid Gene 8 (Stra8) has been found to be required for the transition into meiosis in both female and male germ cells. Stra8 is expressed in embryonic ovaries just before meiotic initiation, whereas its expression in testes is first detected after birth. Here we examine the mechanism underlying the sex-specific timing of Stra8 expression and meiotic initiation in mice. Our work shows that signaling by retinoic acid (RA), an active derivative of vitamin A, is required for Stra8 expression and thereby meiotic initiation in embryonic ovaries. We also discovered that RA is sufficient to induce Stra8 expression in embryonic testes and in vitamin A-deficient adult testes in vivo. Finally, our results show that cytochrome p450 (CYP)-mediated RA metabolism prevents premature Stra8 expression in embryonic testes. Treatment with an inhibitor specific to RA-metabolizing enzymes indicates that a cytochrome p450 from the 26 family (CYP26) is responsible for delaying Stra8 expression in embryonic testes. Sex-specific regulation of RA signaling thus plays an essential role in meiotic initiation in embryonic ovaries and precludes its occurrence in embryonic testes. Because RA signaling regulates Stra8 expression in both embryonic ovaries and adult testes, this portion of the meiotic initiation pathway may be identical in both sexes.
Follicle stages
Antral
Comment
Cyp26b1 mRNA it can be detected in pregranulosa cells at postnatal d 1 and is maintained at relatively high levels in the ovary during the first 10 d after birth before decreasing by d 19. (Kipp et al ).............
SSR 2010 Abstract 65. Expression, Regulation, and Function of Cyp26b1 in the Mouse
Ovary. Jingjing L. Kipp, et al
Cyp26b1 (cytochrome P450, family 26, subfamily b, polypeptide 1) encodes an
enzyme that degrades the potent morphogen retinoic acid (RA). It has well studied
roles in neural development, and has recently been shown to function as a meiosis
inhibitor and germ cell survival factor in the male gonad. However, its expression is
largely lost in the female mouse embryonic gonad around E12.5. I. Cyp26b1 mRNA was found to be
expressed in granulosa cells of follicles at all developmental stages. A striking inverse
correlation between Cyp26b1 and activin beta A mRNA expression within ovarian
follicles and during postnatal development was observed. Activin regulation of
Cyp26b1 levels in vivo was also confirmed in a transgenic mouse model that has
decreased activin expression, and as a consequence exhibits highly elevated Cyp26b1
expression. Functional studies revealed that the Cyp26 inhibitor R115866 had a
stimulatory effect on the proliferation of primary cultured mouse granulosa cells. As
expected, activin A increases the proliferation of these cells, and a similar effect was
observed with RA. Thus, some of the proliferative effects of activin may be mediated
by decreased Cyp26b1, leading to increased RA levels. A pan-retinoic acid receptor
(RAR) inhibitor, AGN194310, abolished the stimulatory effect of either RA or
activin on granulosa cell proliferation, indicating an involvement of RAR-mediated
signaling in both RA and activin-induced granulosa cell proliferation. We conclude
that Cyp26b1 is expressed in the postnatal mouse ovary and is regulated by activin,
and that the activin and RA pathways may interact to regulate mouse granulosa cell
proliferation. This study suggests novel roles for Cyp26b1 in regulating the
development and function of the mammalian ovary.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: unknown Comment: Retinoid signaling determines germ cell fate in mice. Bowles J et al. Germ cells in the mouse embryo can develop as oocytes or spermatogonia, depending on molecular cues that have not been identified. We found that retinoic acid, produced by mesonephroi of both sexes, causes germ cells in the ovary to enter meiosis and initiate oogenesis. Meiosis is retarded in the fetal testis by the action of the retinoid-degrading enzyme CYP26B1, ultimately leading to spermatogenesis. In testes of Cyp26b1-knockout mouse embryos, germ cells enter meiosis precociously, as if in a normal ovary. Thus, precise regulation of retinoid levels during fetal gonad development provides the molecular control mechanism that specifies germ cell fate.
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In Cyp26b1 knockout mice, male germ cells undergo massive apoptosis when meiosis takes place prematurely at embryonic d 13.5 in the testis, whereas female germ cell numbers appear to be normal at birth in the ovary (Maclean G 2007 Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology 148:4560). This observation is not surprising because Cyp26b1 expression is already absent in the normal embryonic ovary at embryonic d 12.5 and meiosis can be initiated normally. No further analysis of postnatal ovary development was carried out in the Cyp26b1 knockout mice because they die shortly after birth.