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Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad.

Childs AJ, Cowan G, Kinnell HL, Anderson RA, Saunders PT - PLoS ONE (2011)

Bottom Line: The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment.Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however.We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. a.childs@ed.ac.uk

ABSTRACT
The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8-9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in regulating the onset of meiosis in the human fetal ovary, mechanisms other than CYP26B1-mediated metabolism of RA may exist to inhibit the entry of germ cells into meiosis in the human fetal testis.

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Expression of genes encoding retinoic acid and retinoid receptors in the human fetal gonad.qRT-PCR analysis of expression of the genes encoding the retinoic acid (RARα (A), RARβ (B) and RARγ (C) and retinoid (RXRα (D), RXRβ (E) and RXRγ (F)) in the human fetal testis and ovary. No significant differences in levels encoding any of the receptor isoforms were detected between samples of different gestational ages within the same sex, or in gonads of different sexes at the same developmental age, indicating that RAR/RXR receptor expression is not developmentally-regulated in the human fetal gonad. Values denote mean ± s.e.m; 8–9, 14–16 and 17–20 denotes gestational age (in weeks) of specimens.
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pone-0020249-g002: Expression of genes encoding retinoic acid and retinoid receptors in the human fetal gonad.qRT-PCR analysis of expression of the genes encoding the retinoic acid (RARα (A), RARβ (B) and RARγ (C) and retinoid (RXRα (D), RXRβ (E) and RXRγ (F)) in the human fetal testis and ovary. No significant differences in levels encoding any of the receptor isoforms were detected between samples of different gestational ages within the same sex, or in gonads of different sexes at the same developmental age, indicating that RAR/RXR receptor expression is not developmentally-regulated in the human fetal gonad. Values denote mean ± s.e.m; 8–9, 14–16 and 17–20 denotes gestational age (in weeks) of specimens.

Mentions: We detected transcripts encoding all three RAR (Figure 2A–C) and RXR (Figure 2D–F) receptors in human fetal testes and ovaries. Interestingly however, we did not detect any significant changes in expression of any of the receptor isoforms either between gonads obtained from fetuses of the same sex at different gestational ages, or between those of different sexes at the same developmental stage (Figure 2A–F, n = 4–6 per group). Expression of the retinoid receptor machinery therefore appears not to be developmentally-regulated at the transcript level in human fetal gonads around the time of meiosis.


Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad.

Childs AJ, Cowan G, Kinnell HL, Anderson RA, Saunders PT - PLoS ONE (2011)

Expression of genes encoding retinoic acid and retinoid receptors in the human fetal gonad.qRT-PCR analysis of expression of the genes encoding the retinoic acid (RARα (A), RARβ (B) and RARγ (C) and retinoid (RXRα (D), RXRβ (E) and RXRγ (F)) in the human fetal testis and ovary. No significant differences in levels encoding any of the receptor isoforms were detected between samples of different gestational ages within the same sex, or in gonads of different sexes at the same developmental age, indicating that RAR/RXR receptor expression is not developmentally-regulated in the human fetal gonad. Values denote mean ± s.e.m; 8–9, 14–16 and 17–20 denotes gestational age (in weeks) of specimens.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108594&req=5

pone-0020249-g002: Expression of genes encoding retinoic acid and retinoid receptors in the human fetal gonad.qRT-PCR analysis of expression of the genes encoding the retinoic acid (RARα (A), RARβ (B) and RARγ (C) and retinoid (RXRα (D), RXRβ (E) and RXRγ (F)) in the human fetal testis and ovary. No significant differences in levels encoding any of the receptor isoforms were detected between samples of different gestational ages within the same sex, or in gonads of different sexes at the same developmental age, indicating that RAR/RXR receptor expression is not developmentally-regulated in the human fetal gonad. Values denote mean ± s.e.m; 8–9, 14–16 and 17–20 denotes gestational age (in weeks) of specimens.
Mentions: We detected transcripts encoding all three RAR (Figure 2A–C) and RXR (Figure 2D–F) receptors in human fetal testes and ovaries. Interestingly however, we did not detect any significant changes in expression of any of the receptor isoforms either between gonads obtained from fetuses of the same sex at different gestational ages, or between those of different sexes at the same developmental stage (Figure 2A–F, n = 4–6 per group). Expression of the retinoid receptor machinery therefore appears not to be developmentally-regulated at the transcript level in human fetal gonads around the time of meiosis.

Bottom Line: The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment.Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however.We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. a.childs@ed.ac.uk

ABSTRACT
The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8-9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in regulating the onset of meiosis in the human fetal ovary, mechanisms other than CYP26B1-mediated metabolism of RA may exist to inhibit the entry of germ cells into meiosis in the human fetal testis.

Show MeSH
Related in: MedlinePlus