Meiosis Initiates In The Fetal Ovary Of Mice Lacking All Retinoic Acid Receptor Isotypes

Abstract

17Gametes are generated through a specialized cell differentiation process, 18 meiosis which, in most mammals, is initiated in ovaries during fetal life. It is widely 19 admitted that all-trans retinoic acid (ATRA) is the molecular signal triggering meiosis 20 initiation in mouse female germ cells, but a genetic approach in which ATRA synthesis 21 is impaired disputes this proposal. In the present study, we investigated the 22 contribution of endogenous ATRA to meiosis by analyzing fetuses lacking all RARs 23 ubiquitously, obtained through a tamoxifen-inducible cre recombinase-mediated gene 24 targeting approach. Efficient ablation of RAR-coding genes was assessed by the 25 multiple congenital abnormalities displayed by the mutant fetuses. Unexpectedly, their 26 germ cells robustly expressed STRA8, REC8, SYCP1 and SYCP3, showing that RAR 27 are actually dispensable up to the zygotene stage of meiotic prophase I. Thus our study 28 goes against the current model according to which meiosis is triggered by endogenous 29 ATRA in the developing ovary and revives the identification of the meiosis-preventing 30 substance synthesized by CYP26B1 in the fetal testis. 32 Mammalian meiosis is a germ-cell specific division process that generates 33 haploid gametes from their diploid precursors, oogonia in the female and 34 spermatogonia in the male. In the mouse, female germ cells enter into meiosis before 35 birth, around embryonic day 13.5 (E13.5) 1 . During the same embryonic period, male 36 germ cells stop proliferating, and enter the G0/G1 phase of the cell cycle thus 37 becoming mitotically quiescent. Male germ cells resume proliferation at birth, and then 38 enter into meiosis starting from post-natal day 8 2 . 39In order to account for the sexual dimorphism in the timing of gem cell 40 differentiation, it was hypothesized, notably from transplantation experiments of germ 41 cells 3 , that the decision to enter meiosis is controlled by a meiosis-inducing substance 42 (MIS) or/and by a meiosis-preventing substance (MPS) produced by somatic cells 4 . 43Subsequently, it was proposed that all-trans retinoic acid (ATRA) and its degrading 44 enzyme CYP26B1 played key roles in controlling the timing of meiosis initiation in 45 female and male gonads, respectively 5,6 . The concept that ATRA is the MIS was 46 however challenged by a genetic study demonstrating that meiosis initiation occurs 47 despite the lack of two major ATRA-synthesizing enzymes 7 . The recent finding that a 48 third enzyme, expressed in fetal ovaries and capable of ATRA synthesis, is also 49 involved in meiosis revived the model according to which meiosis entry is triggered by 50 endogenous ATRA in the ovary 8 51 ATRA is the active metabolite of retinol (vitamin A). Inside cells, conversion of 52 retinol to ATRA depends upon retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2 53 and ALDH1A3 isotypes) 9 . Then, ATRA activity is mediated by the nuclear retinoic acid 54 receptors (RARA, RARB and RARG isotypes), which are ligand-dependent 55 transcr...

Divergent Roles of CYP26B1 and Endogenous Retinoic Acid in Mouse Fetal Gonads

“…Later, RA would reach the STRA8–positive GC and then possibly amplify the transcription of Stra8 . In agreement with this model, it was recently reported that RAR are dispensable for meiosis initiation in mouse fetal ovaries [39]. Following this line, the actual regulator of the meiotic switch, which was previously termed the ‘meiotic preventing substance’, remains to be identified.…”

Single-cell RNA sequencing reveals regulation of fetal ovary development in the monkey (Macaca fascicularis)

“…Previous studies have shown that RA induces the expression of STRA8, which could further switch on the meiotic genes, such as SYCP3, and repress the early PGC program to promote meiosis initiation. RA enhances this pathway through retinoic acid receptor (RAR)-mediated transcriptional regulation; however, after ablation of RARcoding genes, the FGCs robustly expressed meiotic genes, such as STRA8, REC8, and SYCP3, showing that RARs are actually dispensable for meiosis initiation 30 . Moreover, recent studies indicate that Zglp1 is partially overlapped with Nanog in mice, which is sufficient to induce the oogenic fate and meiosis entry, whereas RA augments the ZGLP1-activated oogenic program and meiosis initiation 16,31 .…”