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Retinoic Acid Metabolism and Signaling Pathways in the Adult and Developing Mouse Testis

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (N.V., C.D., C.R.-E., M.O.-A., P.C., N.B.G., M.M.), and Institut Clinique de la Souris (ICS) (P.C., M.M.), Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Louis Pasteur de Strasbourg (ULP)/Collège de France, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg, France

Address all correspondence and requests for reprints to: Manuel Mark, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Louis Pasteur de Strasbourg (ULP)/Collège de France, BP10142, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg, France. E-mail: marek{at}igbmc.u-strasbg.fr.

As a first step in investigating the role of retinoic acid (RA) in mouse testis, we analyzed the distribution pattern of the enzymes involved in vitamin A storage (lecithin:retinol acyltransferase), RA synthesis (ß-carotene 15,15'-monoxygenase and retinaldehyde dehydrogenases) and RA degradation (cytochrome P450 hydroxylases) as well as those of all isotypes of receptors transducing the RA signal [RA receptors (RARs) and rexinoid receptors (RXRs)]. Our data indicate that in adult testis 1) cytochrome P450 hydroxylase enzymes may generate in peritubular myoid cells a catabolic barrier that prevents circulating RA and RA synthesized by Leydig cells to enter the seminiferous epithelium; 2) the compartmentalization of RA synthesis within this epithelium may modulate, through paracrine mechanisms, the coupling between spermatogonia proliferation and spermatogenesis; 3) retinyl esters synthesized in round spermatids by lecithin:retinol acyltransferase may be transferred and stored in Sertoli cells, in the form of adipose differentiation-related protein-coated lipid droplets. We also show that RAR and RXRß are confined to Sertoli cells, whereas RAR is expressed in spermatogonia and RARß, RXR, and RXR are colocalized in step 7–8 spermatids. Correlating these expression patterns with the pathological phenotypes generated in response to RAR and RXR mutations and to postnatal vitamin A deficiency suggests that spermiation requires RXRß/RAR heterodimers in Sertoli cells, whereas spermatogonia proliferation involves, independently of RXR, two distinct RAR-mediated signaling pathways in both Sertoli cells and spermatogonia. Our data also suggest that the involvement of RA in testis development starts when primary spermatogonia first appear.

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