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First published online 22 August 2007
doi: 10.1242/dev.001107

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Retinoic acid, meiosis and germ cell fate in mammals

Division of Molecular Genetics and Development, and ARC Centre of Excellence in Biotechnology and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

View larger version (39K): [in this window] [in a new window]   Fig. 1. The timing of mature gamete production from mouse primordial germ cells. Primordial germ cells (PGCs) are specified at 7.2 dpc and subsequently proliferate and migrate towards the bipotential gonads, which they occupy at 10.5 dpc. In the ovary (pink), at 13.5 dpc, PGCs begin to enter meiosis I (the first meiotic division). Primary oocytes pass through the leptotene, zygotene and pachytene stages before entering diplonema/dictyate arrest at around birth. Once sexual maturity is reached, at each ovulation a cohort of arrested oocytes is stimulated to resume and complete meiosis I and enter meiosis II. The released mature egg is arrested in metaphase II, completing meiosis II after fertilization. In the testis (blue), germ cells do not enter meiosis at 13.5 dpc, but arrest mitotically. Immediately after birth, germ cells re-enter the mitotic cycle and meiosis I is initiated several days later. Both divisions are completed rapidly to produce spermatozoa (sperm). The process is repeated many times throughout life to ensure a continuous supply of mature sperm.

View larger version (19K): [in this window] [in a new window]   Fig. 2. Regulation of germ cell entry into meiosis in the developing gonads. (A) In the bipotential (11.5 dpc) mouse gonad, germ cells are present and retinoic acid (RA) is produced in the mesonephric duct and tubules. Cyp26b1 is expressed at low levels in the gonad of both sexes. The mesonephric tubules, which produce RA, are physically connected with the anterior (Ant) end of the gonad during this time. (Ba) Once Sry is expressed in the male gonad (at 11.5 dpc), Cyp26b1 expression is upregulated, probably in both Sertoli and interstitial cells. The testis cords, which form around germ cell clusters, might concentrate the enzyme in these regions, thereby protecting germ cells from the actions of RA. (Bb) Germ cells in the male gonad do not enter meiosis at 13.5 dpc, and continue to express the pluripotency marker Pou5f1. (Ca) In the female gonad, Cyp26b1 expression is detectable at 11.5 dpc, but disappears by 12.5 dpc. Germ cells at the anterior end of the gonad begin to express Stra8 at 12.5 dpc; (Cb) by 13.5 dpc, later markers of meiosis, such as Sycp3 and Dmc1, are expressed strongly. Meiosis markers are upregulated in an anterior-to-posterior (Post) wave over 3 days. Pou5f1 is no longer expressed by germ cells once they enter meiosis. Germ cells at the anterior end of the gonad might be exposed to RA earlier than those at the posterior end, or the RA concentration might be greater at the anterior end than the posterior end. See text for more details.

View larger version (48K): [in this window] [in a new window]   Fig. 3. Marker gene expression in 13.5 dpc mouse gonads. Urogenital ridge tissue samples were dissected from wild-type mouse embryos. (A) Expression of the pre-meiotic marker Stra8 is absent in male (M, left) but present in female (F, right) 13.5 dpc mouse urogenital ridge samples. Only germ cells, just prior to entry into meiosis, express this marker gene and higher expression is seen in germ cells located at the anterior (top) end of the gonad. (B) Expression of the pluripotency marker Pou5f1 (Oct4) in male and female 13.5 dpc mouse urogenital ridge samples. Only premeiotic germ cells express this gene at this stage of development. Staining highlights the clustering of germ cells in the male sample in testis cord structures and the dispersal of germ cells in the female sample. Germ cells are present throughout the length of the female gonad, but Pou5f1 expression has been downregulated at the anterior (top) end at this stage (see text). g, gonad; m, mesonephros.

View larger version (16K): [in this window] [in a new window]   Fig. 4. A model of RA regulation during prenatal and postnatal meiosis. (A) Schematic of a 12.5 dpc female urogenital ridge (UGR). The mesonephros produces an RA-synthesizing enzyme (RALDH2). We postulate that retinoic acid (RA) moves from the mesonephros into the adjacent gonad through open mesonephric tubules. Germ cells resident in the female gonad express RA receptors (RARs) and respond to RA by expressing STRA8. (B) Schematic of a 12.5 dpc male UGR. The RA-degrading enzyme CYP26B1 is produced by somatic cells. We postulate that, although all germ cells express RARs and thus can respond to RA, they are not exposed to sufficient amounts of RA to induce STRA8 production. (C) Schematized cross-section of a seminiferous tubule at 10 days post partum (10 dpp). CYP26 enzymes (CYP26A1, CYP26B1 and CYP26C1) are produced by peritubular myoid (PM) cells, which surround and isolate seminiferous tubules from the rest of the body. Within the seminiferous tubules, Sertoli cells produce RALDH enzymes (RALDH1 and RALDH2) and germ cells express RARs. As germ cells enter meiosis they produce STRA8. We postulate that RA, produced locally within the seminiferous tubules, triggers Stra8 expression in germ cells and, hence, triggers entry into meiosis.