The vitamin A derivative retinoic acid is known to be a potent agent for control of differentiation and proliferation of
epithelial cells and to exert profound effects on pattern formation during embryogenesis. Its action at the molecular level
appears to be mediated by two distinct classes of proteins: a family of nuclear receptors that regulates gene
transcription in a ligand-dependent fashion and a small cellular retinoic acid-binding protein (CRABP) for which a
precise function remains to be elucidated.
Petkovich et al. (1987) cloned a cDNA encoding a protein that binds retinoic acid with high affinity. The protein was
found to be homologous to the receptors for steroid hormones, thyroid hormones, and vitamin D3, and appeared to be a
retinoic acid-inducible transacting enhancer factor. Thus, the molecular mechanisms of the effect of vitamin A on
embryonic development, differentiation and tumor cell growth may be similar to those described for other members of
this nuclear receptor family.
NCBI Summary:
This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]
General function
Receptor, Nucleic acid binding, DNA binding, Transcription factor
Comment
Analysis of Follicular Fluid Retinoids in Women Undergoing In Vitro Fertilization: Retinoic Acid Influences Embryo Quality and Is Reduced in Women With Endometriosis. Pauli SA et al. Retinol (ROL) and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. The objectives of this study were to quantify and compare peripheral plasma (PP) and follicular fluid (FF) retinoid levels, including ATRA in women undergoing in vitro fertilization (IVF) and to investigate the relationship between retinoid levels and embryo quality. Retinoid levels were evaluated in PP and FF from 79 women undergoing IVF at the time of oocyte retrieval and corresponding embryo quality assessed on a daily basis after retrieval for 3 days until uterine transfer. Analysis compared the retinoid levels with day 3 embryo grades and between endometriosis versus control patients. Results demonstrated distinctive levels of retinoid metabolites and isomers in FF versus PP. There was a significantly larger percentage of high-quality grade I embryos derived from the largest versus smallest follicles. An increase in follicle size also correlated with a >50% increase in FF ROL and ATRA concentrations. Independent of follicle size, FF yielding grade I versus nongrade I embryos showed higher mean levels of ATRA but not ROL. In a nested case-control analysis, control participants had 50% higher mean levels of ATRA in their FF and PP than women with endometriosis. These findings strongly support the proposition that ATRA plays a fundamental role in oocyte development and quality, and that reduced ATRA synthesis may contribute to decreased fecundity of participants with endometriosis.
Cellular localization
Nuclear
Comment
Ovarian function
Follicle development, Follicle atresia, Steroid metabolism, Oogenesis, Oocyte maturation, Early embryo development
Comment
Retinoic acid enhances progesterone production via the cAMP/PKA signaling pathway in immature rat granulosa cells. Suwa H et al. (2018) Retinoic acid (RA) is a metabolite of vitamin A and has important roles in development, differentiation, and reproduction. Activin has been shown to regulate the RA pathway and affect granulosa cell (GC) proliferation, suggesting that RA is important for early follicle development. However, little is known about the effects of RA on GC functions, particularly steroidogenesis, during the early follicle stage. The aim of this study was to investigate the effects of all-trans-RA (atRA) on progesterone production in immature rat GCs cultured without gonadotropin. Our results demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein (StAR) and cytochrome P450scc (Cyp11a1) mRNAs, but not 3β-hydroxysteroid dehydrogenase mRNA in immature rat GCs. Additionally, analysis of the mechanisms through which atRA upregulatedStARandCyp11a1mRNAs revealed that atRA enhanced intracellular cAMP accumulation and phosphorylation of cAMP response-element binding protein (CREB). In addition, H-89, an inhibitor of protein kinase A (PKA), abolished the stimulatory effects of atRA, indicating that atRA enhanced progesterone synthesis through cAMP/PKA signaling. In conclusion, our data demonstrated that atRA has a crucial role in progesterone synthesis in rat GCs during the early follicle stage.//////////////////
Retinoic Acid Regulates Calcium Signaling to Promote Mouse Ovarian Granulosa Cell Proliferation. Demczuk M et al. (2016) Normal development of ovarian follicles is critical for female reproduction and endocrine function. We have identified retinoic acid (RA) and the RA-degrading enzyme CYP26B1 as regulators of ovarian follicle development and shown that RA and a CYP26 inhibitor stimulate ovarian granulosa cell proliferation. The mechanism underpinning RA-dependent proliferation, however, is not known. The current study was designed to examine the role of intracellular calcium (Ca(2+)) signaling in mediating the effects of RA on primary mouse granulosa cell proliferation. In single-cell Ca(2+) imaging experiments, treatment of cultured granulosa cells with RA increased the steady-state Ca(2+) content of the endoplasmic reticulum (ER) stores. This correlated with increased store-operated Ca(2+) entry (SOCE) and enhanced inositol 1,4,5-trisphosphate receptor (IP3R)-dependent Ca(2+) release. In proliferation assays, RA treatment or Cyp26b1 knockdown stimulated while Cyp26b1 overexpression inhibited proliferation. When RA was given together with 2-Aminoethoxydiphenylborane (2-APB), a blocker of IP3R-dependent ER Ca(2+) release and SOCE, with Xestospongin C, a selective IP3R- receptor antagonist, or with 3,5-bis(trifluoromethyl)pyrazole (BTP-2), a specific SOCE blocker, the stimulatory effect of RA on cell proliferation was abolished. Further investigation showed that treatment with 2-APB or BTP-2 inhibited RA induction of RA response element (RARE) activation in granulosa cells, confirming an important role for Ca(2+) signaling in mediating RA actions. Overall, these data support a model in which RA regulates ovarian follicle development by stimulating granulosa cell proliferation and this stimulatory effect is at least in part driven by the modulation of Ca(2+) signaling.//////////////////
All-trans retinoic acid improves goat oocyte nuclear maturation and reduces apoptotic cumulus cells during in vitro maturation. Pu Y 2014 et al.
All-trans retinoic acid (t-RA) is a natural component and representative physiologically active metabolite of vitamin A, having multiple physiologic functions. The objective of this study was to evaluate the effect of t-RA on goat oocyte maturation and cumulus cell apoptosis during in vitro maturation (IVM). Immature goat cumulus-oocyte complexes (COCs) were matured in vitro in the absence or presence of t-RA at concentrations of 10?nmol/L, 100?nmol/L and 1000?nmol/L. Oocyte maturation and embryo development were assessed by polar body formation and parthenogenetic activation, respectively. Oocyte survival was checked by Trypan blue staining. Apoptosis of cumulus cells was analyzed by terminal deoxynucleotidyl transferase nick end labeling staining and quantitative real-time PCR. In comparison with the control group, 100?nmol/L and 10?nmol/L t-RA significantly improved goat nuclear oocyte maturation and survival (P?Liang S et al. Retinoids have important roles in regulation of oocyte nuclear and cytoplasmic maturation. The present study investigated the effects of a retinoid metabolite on nuclear maturation, cytoplasmic maturation, and gene expression in canine oocytes during in vitro maturation (IVM). Cumulus-oocyte complexes (COCs) were harvested from ovaries by slicing. Only oocytes that were >120 ?m in diameter, with a homogeneous dark cytoplasm and three or more layers of compact cumulus cells were used. Varying concentrations of 9-cis retinoic acid (9-cis-RA; 0, 5, 50, and 500 nm) were included in the maturation medium, and the following were measured: (i) oocyte nuclear maturation after culture for 48 h; (ii) cytoplasmic granular migration by labeling of oocytes with fluorescein isothiocyanate labeled lectins; and (iii) relative expression of genes related to apoptosis (BAX and BclII) in cumulus cells detached from oocytes, by semiquantitative reverse transcriptase-polymerase chain reaction. After 48 h culture with IVM, the highest percentage of oocytes that had developed to the metaphase II (MII) stage were in the 5 nm 9-cis-RA treatment group (18.3 ? 2.5%; P < 0.05). Complete granular migration was observed in oocytes matured with 5 nm 9-cis-RA, consistent with a commensurate gain in developmental competence. Treatment with 5 nm 9-cis-RA had no effect on BclII gene expression, but downregulated BAX expression. In conclusion, since 5 nm 9-cis-RA was beneficial to nuclear and cytoplasmic maturation of canine oocytes, we inferred an important role for 9-cis-RA during IVM.
9-cis retinoic acid inhibits cumulus cell apoptosis during the maturation of bovine cumulus-oocyte-complexes. Deb GK et al. Cumulus cell (CC) apoptosis is inversely correlated with embryonic development in vitro. Therefore, inhibition of CC apoptosis is important for proper embryonic development and quality. Retinoic acids (all-transRA and 9-cisRA) are the natural components of retinoids and the 9-cisRA is the physiologically active metabolite of retinoic acid in vitro. During in vitro maturation, 9-cisRA enhances oocyte competence through multiple mechanisms affecting the oocyte and the preimplantation embryo; however, the effect of 9-cisRA on CC apoptosis has yet to be elucidated. The aim of the present study was to evaluate the effect of 9-cisRA on CC apoptosis and to identify the molecular mechanism underlying that effect. Bovine slaughterhouse cumulus-oocyte-complexes (COC) were matured in vitro in the absence or presence of 5 nM 9-cisRA. Cumulus cells were collected from immature and matured COC for the detection of apoptosis and gene expression analysis. Results showed that 9-cisRA reduced the number of apoptotic CC by about 2.7-fold (P < 0.023) compared to the control. However, apoptosis is rare in CC of immature COC (0.01% ? 0.001). Transcripts involved in the caspase cascade were down-regulated upon exposure to 9-cisRA, including tumor necrosis factor alpha (TNF-a, 11.1-fold, P < 0.001), tumor necrosis factor alpha receptor 1 (TNFR1, 2.3-fold, P < 0.01), caspase 9 (CASP9, 2.0-fold, P < 0.031), caspase 8 (CASP8, 2.2-fold, P < 0.012), and caspase 3 (CASP3, 2.1-fold, P < 0.006), while anti-apoptotic B-cell lymphoma 2 (BCL2) transcript was increased (3.1-fold, P < 0.004) compared to the control. In addition, 9-cisRA inhibited mitogen activated protein kinase mRNA expression in CC, including extracellular signal-regulated kinase 1/2 (ERK1, 2.7-fold, P < 0.02; ERK2, 2.7-fold, P < 0.03), and c-Jun N-terminal kinase (JNK, 1.6-fold, P < 0.044), as well as the activator protein-1 (AP1) family members c-jun (1.6-fold, P < 0.041) and c-fos (2.0-fold, P < 0.06). The transcript abundances of TNF-a, TNFR1, CASP9, CASP8, CASP3, ERK1, ERK1, JNK, and BCL2 were increased while c-fos and c-jun mRNA expression was decreased in the matured CC. In conclusion, the present study suggests that 9-cisRA inhibits CC apoptosis during in vitro maturation of bovine COC.
Retinoic acid derived from the fetal ovary initiates meiosis in mouse germ cells. Mu X et al. Meiotic initiation of germ cells at 13.5 dpc (days post-coitus) indicates female sex determination in mice. Recent studies reveal that mesonephroi-derived retinoic acid (RA) is the key signal for induction of meiosis. However, whether the mesonephroi is dispensable for meiosis is unclear and the role of the ovary in this meiotic process remains to be clarified. This study provides data that RA derived from fetal ovaries is sufficient to induce germ cell meiosis in a fetal ovary culture system. When fetal ovaries were collected from 11.5 dpc to 13.5 dpc fetuses, isolated and cultured in vitro, germ cells enter meiosis in the absence of mesonephroi. To exclude RA sourcing from mesonephroi, 11.5 dpc urogenital ridges (UGRs; mesonephroi and ovary complexes) were treated with diethylaminobenzaldehyde (DEAB) to block retinaldehyde dehydrogenase (RALDH) activity in the mesonephros and the ovary. Meiosis occurred when DEAB was withdrawn and the mesonephros was removed two days later. Furthermore, RALDH1, rather than RALDH2, serves as the major RA synthetase in UGRs from 12.5 dpc to 15.5 dpc. DEAB treatment to the ovary alone was able to block germ cell meiotic entry. We also found that exogenously supplied RA dose-dependently reduced germ cell number in ovaries by accelerating the entry into meiosis. These results suggest that ovary-derived RA is responsible for meiosis initiation. J. Cell. Physiol. ? 2012 Wiley Periodicals, Inc.
Effects of retinoic acid on maturation of immature mouse oocytes in the presence and absence of a granulosa cell co-culture system. Tahaei LS et al. PURPOSE: Evaluation of the all-trans retinoic acid (t-RA) effects on in vitro maturation (IVM) and in vitro fertilization (IVF) of immature mouse oocytes in the presence and absence of granulosa cell monolayer. METHODS: Denuded oocytes isolated from mice ovaries and matured in IVM medium alone (Control I), IVM medium in the presence of granulosa cells (Control II), IVM medium with t-RA (Experimental I) and IVM medium simultaneously with t-RA and granulosa cells (Experimental II). After 24?h, matured oocytes were fertilized in T6 medium and their development was followed until the blastocyst stage. Metaphase II oocytes ploidy were evaluated by chromosome counting. RESULTS: The t-RA group compared to the control groups showed no obvious abnormalities. Additionally maturation and embryo development rates significantly increased in the t-RA treated granulosa cell co-culture system. CONCLUSIONS: In conclusion, association of t-RA with granulosa cell co-culture during in vitro maturation increases meiosis resumption, formation of metaphase II oocytes, as well as 2-cell and blastocyst stage embryos.
The 9-Cis Retinoic Acid Signaling Pathway and Its Regulation of Prostaglandin-Endoperoxide Synthase 2 During In Vitro Maturation of Pig Cumulus Cell-Oocyte Complexes and Effects on Parthenogenetic Embryo Production. Atikuzzaman M et al. The addition of 9-cis retinoic acid to the oocyte maturation culture medium has a beneficial effect on in vitro fertilized embryos. However, the mechanism of this activity is not known. Therefore, this study was done to elucidate the effect of 9-cis retinoic acid on parthenogenetic embryo production and its signaling pathway and its molecular function during in vitro maturation of porcine cumulus cell-oocyte complexes (COCs). Concentrations of 0, 5, 50, and 500 nM 9-cis retinoic acid were added to the in vitro maturation medium and embryos were assessed after parthenogenetic activation. Cumulus cells and oocytes from the in vitro matured COCs were separated and subjected to reverse transcription polymerase chain reaction and real time reverse transcription polymerase chain reaction for detecting retinoic acid receptors and measuring expression of prostaglandin-endoperoxide synthase1 and 2. The addition of 5 nM 9-cis retinoic acid to maturation medium was beneficial for parthenogenetic embryo production. The effect of 9-cis retinoic acid was exerted directly through the oocytes via the retinoic acid receptor alpha and retinoid X receptor gamma signaling pathways and indirectly through the cumulus cells by the retinoic acid receptor beta and gamma and retinoid X receptor alpha and beta signaling pathways. The addition of 5 nM 9-cis retinoic acid stimulated cumulus cells reaches full expansion by suppressing their excessive expression of prostaglandin-endoperoxide synthase 2. This study shows that 9-cis retinoic acid can exert its beneficial effect on parthenogenetic embryo production in pigs by multidimensional pathways affecting oocyte maturation.
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.
Minegishi T et al reported that retinoic acid (RA) represses follicle stimulating hormone (FSH)-induced luteinizing hormone (LH) receptor in cultured rat
granulosa cells.
Treatment with FSH produced a substantial increase in LH-R
mRNA level, as was expected, while concurrent treatment with increasing
concentrations of RA brought about dose-dependent decreases in FSH-induced
LH-R mRNA. RA, either alone or in combination with FSH, did not affect
intracellular cAMP levels, while it inhibited the effect of 8-Br-cAMP on LH-R
mRNA production.
Expression regulated by
FSH
Comment
Activity of Retinoic Acid Receptor-{alpha} Is Directly Regulated at Its Protein Kinase A Sites in Response to Follicle-Stimulating Hormone Signaling. Santos NC et al. Retinoic acid receptor-alpha (RARA) is crucial for germ cell development in the testis, as shown by the degenerated testis in Rara gene knockout mice, which are sterile. Similarly, FSH is known to regulate Sertoli cell proliferation and differentiation, indirectly controlling the quantity of the spermatogenic output. Interestingly, FSH inhibited, via activation of FSH receptor, cAMP, and protein kinase A (PKA), the nuclear localization and transcriptional activity of RARA. Given that retinoic acid, the ligand for RARA, is known to regulate cell proliferation and differentiation, we investigated whether FSH regulates RARA by a direct posttranslational phosphorylation mechanism. Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. The negative charges at the PKA sites, whether they are from glutamic acids or phosphorylation of serines, decreased the nuclear localization of RARA, heterodimerization with retinoid X receptor-alpha, and the transcriptional activity of the receptor. On the other hand, the double-alanine mutant that cannot be phosphorylated at the 219 and 369 amino acid positions did not respond to cAMP and PKA activation. Wild-type and double-mutant RARA interacted with PKA, but only in the presence of cAMP or FSH. These results together suggest that FSH may regulate cell proliferation and differentiation of Sertoli cells, at least partially, by directly affecting the PKA sites of RARA and controlling the transcriptional function of the receptor.
Zhuang YH, et al raised an antibody against a synthetic peptide corresponding to amino acids 155-174 of human retinoic acid receptor alpha (RAR-alpha). The sequence is highly homologous in all RARs and their
isoforms. Using immunohistochemistry the RARs
were found in the nuclear compartment. In the rat ovary, positive reaction was found
in the nuclei of germinal epithelial, follicular and stromal cells. Mohan M, et al reported that bovine cumulus-granulosa cells contain biologically active retinoid receptors that can respond to retinoic acid.
Retinoids, a class of compounds that include retinol and its metabolite, retinoic acid, are absolutely essential for ovarian steroid production, oocyte maturation, and early embryogenesis. Previous studies have detected high concentrations of retinol in bovine large follicles. Further, administration of retinol in vivo and supplementation of retinoic acid during in vitro maturation results in enhanced embryonic development. In the present study, we hypothesized that retinoids administered either in vivo previously or in vitro can exert receptor-mediated effects in cumulus-granulosa cells. Total RNA extracted from in vitro cultured cumulus-granulosa cells was subjected to reverse transcription polymerase chain reaction (RT-PCR) and mRNA expression for RARalpha, RARbeta, RARgamma, RXRalpha, RXRbeta, RALDH-2, and PPARgamma. Transcripts were detected for RBP, RARalpha, RARgamma, RXRalpha, RXRbeta, RALDH-2, and PPARgamma. Expression of RARbeta was not detected in cumulus-granulosa cells. Using western blotting, immunoreactive RARalpha, and RXRbeta protein was also detected in bovine cumulus-granulosa cells. The biological activity of these endogenous retinoid receptors was tested using a transient reporter assay using the pAAV-MCS-betaRARE-Luc vector. Addition of 0.5 and 1 uM all-trans retinoic acid significantly (P < 0.05) increased the activity of the pAAV-MCS-betaRARE-Luc reporter compared to cells transfected with the control reporter lacking a retinoic acid response element. Addition of 5 or 10 uM all-trans retinol stimulated a mild increase in reporter activity, however, the increase was not statistically significant. Based on these results we conclude that cumulus cells contain endogenously active retinoid receptors and may also be competent to synthesize retinoic acid using the precursor, retinol. These results also indirectly provide evidence that retinoids administered either in vivo previously or in vitro may have exerted a receptor-mediated effect on cumulus-granulosa cells.
Follicle stages
Comment
Phenotypes
Mutations
3 mutations
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary. Minkina A et al. (2017) Retinoic acid (RA) is a potent inducer of cell differentiation and plays an essential role in sex-specific germ cell development in the mammalian gonad. RA is essential for male gametogenesis and hence fertility. However, RA can also disrupt sexual cell fate in somatic cells of the testis, promoting transdifferentiation of male Sertoli cells to female granulosa-like cells when the male sexual regulator Dmrt1 is absent. The feminizing ability of RA in the Dmrt1 mutant somatic testis suggests that RA might normally play a role in somatic cell differentiation or cell fate maintenance in the ovary. To test for this possibility we disrupted RA signaling in somatic cells of the early fetal ovary using three genetic strategies and one pharmaceutical approach. We found that deleting all three RA receptors (RARs) in the XX somatic gonad at the time of sex determination did not significantly affect ovarian differentiation, follicle development, or female fertility. Transcriptome analysis of adult triple mutant ovaries revealed remarkably little effect on gene expression in the absence of somatic RAR function. Likewise, deletion of three RA synthesis enzymes (Aldh1a1-3) at the time of sex determination did not masculinize the ovary. A dominant-negative RAR transgene altered granulosa cell proliferation, likely due to interference with a non-RA signaling pathway, but did not prevent granulosa cell specification and oogenesis or abolish fertility. Finally, culture of fetal XX gonads with an RAR antagonist blocked germ cell meiotic initiation but did not disrupt sex-biased gene expression. We conclude that RA signaling, although crucial in the ovary for meiotic initiation, is not required for granulosa cell specification, differentiation, or reproductive function.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. Vernet N et al. (2020) Gametes are generated through a specialized cell differentiation process, meiosis, which, in ovaries of most mammals, is initiated during fetal life. All-trans retinoic acid (ATRA) is considered as the molecular signal triggering meiosis initiation. In the present study, we analyzed female fetuses ubiquitously lacking all ATRA nuclear receptors (RAR), obtained through a tamoxifen-inducible cre recombinase-mediated gene targeting approach. Unexpectedly, mutant oocytes robustly expressed meiotic genes, including the meiotic gatekeeper STRA8. In addition, ovaries from mutant fetuses grafted into adult recipient females yielded offspring bearing null alleles for all Rar genes. Thus, our results show that RAR are fully dispensable for meiotic initiation, as well as for the production of functional oocytes. Assuming that the effects of ATRA all rely on RAR, our study goes against the current model according to which meiosis is triggered by endogenous ATRA in the developing ovary. It therefore revives the search for the meiosis-inducing substance.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. Vernet N et al. (2020) Gametes are generated through a specialized cell differentiation process, meiosis, which, in ovaries of most mammals, is initiated during fetal life. All-trans retinoic acid (ATRA) is considered as the molecular signal triggering meiosis initiation. In the present study, we analyzed female fetuses ubiquitously lacking all ATRA nuclear receptors (RAR), obtained through a tamoxifen-inducible cre recombinase-mediated gene targeting approach. Unexpectedly, mutant oocytes robustly expressed meiotic genes, including the meiotic gatekeeper STRA8. In addition, ovaries from mutant fetuses grafted into adult recipient females yielded offspring bearing null alleles for all Rar genes. Thus, our results show that RAR are fully dispensable for meiotic initiation, as well as for the production of functional oocytes. Assuming that the effects of ATRA all rely on RAR, our study goes against the current model according to which meiosis is triggered by endogenous ATRA in the developing ovary. It therefore revives the search for the meiosis-inducing substance.//////////////////