Vitamin A Deficiency Blocks the Initiation of Meiosis of Germ Cells in the Developing Rat Ovary In Vivo. Li H et al. Vitamin A (retinol) is required for male and female reproduction as well as to support many developmental processes. In the male, meiotic entry of germ cells occurs after birth and throughout adulthood, whereas in the female the entry into meiosis I occurs during embryonic development. Evidence from cultured embryonic ovaries suggests that the vitamin A metabolite, all-trans retinoic acid (atRA), initiates this process. However, in vivo evidence to support a normal role for atRA in meiotic entry is lacking. The present study demonstates that, although germ cell number is normal in ovaries from both vitamin A sufficient (VAS) embryos and those that are deficient in atRA, the majority of germ cells in the most severely atRA-deficient group fail to enter meiosis and remain in an undifferentiated state. In contrast, in a group that is only moderately deficient in atRA, a small number of ovarian germ cells enter meiosis (30%) compared to 75% of cells in the VAS control group. The expression of the atRA-responsive gene, Stra8, is reduced by approximately 90% and 50% in the severely and moderately atRA-deficient ovaries, respectively, compared to the VAS controls. These results provide the first in vivo evidence that vitamin A regulates the entry of germ cells into meiosis in the developing ovary.
Expression regulated by
Growth Factors/ cytokines, wnt
Comment
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.
Ovarian localization
Primordial Germ Cell
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
Comment
Comparative gene expression profiling of adult mouse ovary-derived oogonial stem cells supports a distinct cellular identity. Imudia AN 2013 et al.
OBJECTIVE
Perform gene expression profiling of adult mouse ovary-derived oogonial stem cells (OSCs).
DESIGN
Experimental animal study.
SETTING
Research laboratory.
ANIMAL(S)
Adult C57BL/6 female mice.
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
Gene expression profiles were compared between freshly isolated and cultured OSCs, as well as between OSCs and embryonic stem cells (ESCs), fetal primordial germ cells (PGCs), and spermatogonial stem cells (SSCs); OSC yield from ovaries versus meiotic gene activation during the estrous cycle was determined.
RESULT(S)
Freshly isolated OSCs, PGCs, and SSCs exhibited distinct gene expression profiles. Cultured OSCs maintained their germline gene expression pattern but gained expression of pluripotency markers found in PGCs and ESCs. Cultured OSCs also expressed the meiotic marker, stimulated by retinoic acid gene 8 (Stra8). Invivo, OSC yield was higher from luteal versus follicular phase ovaries, and this was inversely related to Stra8 expression.
CONCLUSION(S)
Freshly isolated OSCs exhibit a germline gene expression profile that overlaps with, but is distinct from, that of PGCs and SSCs. After invitro expansion, OSCs activate expression of pluripotency genes found in freshly isolated PGCs. Invivo, OSC numbers in the ovaries fluctuate during the estrous cycle, with the highest numbers noted during the luteal phase. This is followed by activation of Stra8 expression during the follicular phase, which may signify a wave of neo-oogenesis to partially offset follicular loss through atresia and ovulation in the prior cycle.
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Oocyte differentiation is genetically dissociable from meiosis in mice. Dokshin GA et al. Oogenesis is the process by which ovarian germ cells undertake meiosis and differentiate to become eggs. In mice, Stra8 is required for the chromosomal events of meiosis to occur, but its role in differentiation remains unknown. Here we report Stra8-deficient ovarian germ cells that grow and differentiate into oocyte-like cells that synthesize zonae pellucidae, organize surrounding somatic cells into follicles, are ovulated in response to hormonal stimulation, undergo asymmetric cell division to produce a polar body and cleave to form two-cell embryos upon fertilization. These events occur without premeiotic chromosomal replication, sister chromatid cohesion, synapsis or recombination. Thus, oocyte growth and differentiation are genetically dissociable from the chromosomal events of meiosis. These findings open to study the independent contributions of meiosis and oocyte differentiation to the making of a functional egg.