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

Laura Bellutti,Delphine Moison,Marie-Justine Guerquin,Virginie Rouiller-Fabre,Emilie Abby,Sophie Tourpin,Sébastien Messiaen,René Habert,Gabriel Livera,Emilie Trautmann

doi:10.3390/biom9100536

Abstract

In female mammals, germ cells enter meiosis in the fetal ovaries, while in males, meiosis is prevented until postnatal development. Retinoic acid (RA) is considered the main inducer of meiotic entry, as it stimulates Stra8 which is required for the mitotic/meiotic switch. In fetal testes, the RA-degrading enzyme CYP26B1 prevents meiosis initiation. However, the role of endogenous RA in female meiosis entry has never been demonstrated in vivo. In this study, we demonstrate that some effects of RA in mouse fetal gonads are not recapitulated by the invalidation or up-regulation of CYP26B1. In organ culture of fetal testes, RA stimulates testosterone production and inhibits Sertoli cell proliferation. In the ovaries, short-term inhibition of RA-signaling does not decrease Stra8 expression. We develop a gain-of-function model to express CYP26A1 or CYP26B1. Only CYP26B1 fully prevents STRA8 induction in female germ cells, confirming its role as part of the meiotic prevention machinery. CYP26A1, a very potent RA degrading enzyme, does not impair the formation of STRA8-positive cells, but decreases Stra8 transcription. Collectively, our data reveal that CYP26B1 has other activities apart from metabolizing RA in fetal gonads and suggest a role of endogenous RA in amplifying Stra8, rather than being the initial inducer of Stra8. These findings should reactivate the quest to identify meiotic preventing or inducing substances.

Highlights

Germ cells (GC) are unique in their ability to switch from a mitotic to a meiotic program, which is a crucial feature for gamete production
Retinoic acid (RA) binds nuclear RA receptors (RAR), which act as transcription factors to activate RA-target genes
Rar genes have been reported to be expressed in embryonic germ cells, but their expression in somatic gonadal cells has not been detailed during development

Summary

Introduction

Germ cells (GC) are unique in their ability to switch from a mitotic to a meiotic program, which is a crucial feature for gamete production. The timing of meiotic entry is sexually dichotomic, taking place during fetal life in the ovaries and during postnatal life in the testes. The different fates of male and female fetal GC are influenced and regulated by the somatic environment, independently of their genetic sex (XX or XY) [1,2,3]. The somatic cells of the developing testes repress meiotic entry, while those of the embryonic ovary license GC to initiate meiosis. Stimulated by RA gene 8 (Stra8) is considered as key regulator of meiotic entry. In both males and females, meiotic initiation is preceded by the expression of Stra. The crucial role of STRA8 in the mitosis/meiosis transition has been highlighted in vivo by analysis of Stra8 −/−

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