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Retinoid Signaling Determines Germ Cell Fate in Mice« Back to Volume 22, Issue 4, December 2006 - Table of Contents The investigators have examined the mechanism(s) that foster germ cell differentiation into oocytes or spermatogonia. During this process the germ cell undergoes the first meiotic division during which the number of chromosomes per cell is halved from the diploid to the haploid number. In the mouse, germ cells undergoing the first meiotic division 13.5 days post coitum (dpc) become oocytes, while germ cells that undergo first meiosis shortly after birth become spermatogonia, suggesting the presence of a “meiosis-inhibiting factor” that regulates the timing of the first meiotic division and hence germ cell differentiation. Searching for gender-related genes expressed in the gonads during mid gestation, the investigators identified male-specific expression of Cyp26b1 in Sertoli cells at 12.5 dpc that was maximal at 13.5 dpc. Cyp26b1 is a P450 cytochrome enzyme that converts all-trans-retinoic acid to polar metabolites increasing their water solubility and enabling their urinary excretion. This transcription factor was present in large amounts in mesonephric cells (the site of its synthesis) as well as in the ovary between 12.5–14.5 dpc; all-trans-retinoic acid levels in the testis at this time were low. In vitro culture of the urogenital ridge (UGR) complex of mesoneophros and gonad revealed that specific molecular indicators of meiosis could be stimulated in the male UGR at 12.5 dpc by addition of all trans-retinoic acid to the culture. In a complementary study, inhibition of retinoic acid action in female UGR prevented expression of meiotic markers. In male mice embryos in which Cyb26b1 had been “knocked out” (and thus cellular retinoic acid levels maintained), germ cell meiosis occurred at 13.5 dpc (in these animals there are also malformations of the limbs). The authors therefore concluded that 1) retinoic acid synthesized by mesonephric cells is the endogenous signal for entry of undifferentiated germs cells into the first meiotic division and 2) by destroying retinoic acid, Cyp26b1 is the meiosis-inhibiting factor that delays germ cell meiosis in the XY mouse and directs germ cell differentiation into spermatogonia. Editor’s CommentGerm cells originate in the epiblast, migrate through the primitive streak to the allantois and then into the urogenital ridge where the gonads form.1 Structural organization of the bipotential urogenital ridge into either ovary or testis is dependent upon a number of factors including WT1, SF1, WNT4, SRY, SOX9, DAX1, and so forth, and occurs during mid gestation in the mouse and in the first trimester of pregnancy in humans. The manner in which bipotential germ cells differentiate into oocytes or spermatogonia had heretofore been unknown. It now appears that all-trans-retinoic acid is a fundamental stimulus to this process and that the activity of retinoic acid is regulated by its rate of degradation by the amount of Cyp26b1 produced by the Sertoli cells of the testis. Interestingly, later in testicular development, all-trans-retinoic acid increases the rate of apoptosis of spermatogonia and thus decreases their number.2 Many questions remain such as: How does early meiosis favor oocyte generation? What is the mechanism by which expression of Cyp26b1 is maintained in the ovary and decreased in the testis until the first meiotic division occurs in the male germ cell? The application of these findings to the study of patients with disorders of sex development (ie, intersex problems) is anticipated. These observations may also be of use in the evaluation of males with disorders of spermatogenesis or females with abnormalities of oogenesis. Might CYPB261 (OMIM 605207) be an oocyte maintenance factor in normal females and be abnormal in girls with gonadal dysgenesis and/or in adult women with premature ovarian failure? Allen W. Root, MD References - (linked to
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
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