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.
Highlights
Primordial germ cells (PGCs) are the embryonic precursors of sperm and egg in the adult organism
We examined the expression of retinoic acid (RA) synthesis enzymes ALDH1A1, ALDH1A2 and ALDH1A3 at three gestational stages which broadly reflect the timing of key events in the development of the human fetal gonad
Whilst meiosis is thought to initiate at the cranial end of the fetal ovary in the human [21], within weeks a radial distribution of germ cells is detectable, with undifferentiated premeiotic PGC-like cells found at the periphery of the ovary and progressively more differentiated germ cells found towards the central cortex [16,17]
Summary
Primordial germ cells (PGCs) are the embryonic precursors of sperm and egg in the adult organism. With the capacity to adopt spermatogenic or oogeneic fates, the developmental trajectory of PGCs is dictated by the somatic sex of the gonad in which they find themselves following migration [1]. Recent data have suggested that meiosis is initiated in the fetal mouse ovary by retinoic acid (RA) signalling, which acts on germ cells to promote the expression of Stimulated by Retinoic Acid (Stra8) [3,4], a protein required for pre-meiotic DNA replication [5]. Germ cells in the fetal mouse testes are shielded from the meiosis-inducing action of RA, first by somatic cell expression of the RAmetabolising enzyme Cyp26b1 [3,4], subsequently by the action of the germ cell-expressed RNA-binding protein Nanos, which acts to ‘lock in’ the male germ cell differentiation program and repress Stra expression in testicular germ cells following the downregulation of Cyp26b1 [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
