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The Effect of 9-cis-Retinoic Acid on Proliferation and Differentiation of A Spermatogonia and Retinoid Receptor Gene Expression in the Vitamin A-Deficient Mouse Testis¹

Department of Cell Biology (I.C.G., A.M.M.v.P., B.H.G.J.S., D.G.d.R.), Medical School, Utrecht University, Utrecht, The Netherlands; Hubrecht Laboratory (E.S., P.T.v.d.S.), Netherlands Institute for Developmental Biology, Utrecht, The Netherlands; Department of Endocrinology and Reproduction, Erasmus University Rotterdam (A.P.N.T.), Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. I. C. Gaemers, Netherlands Cancer Institute, Section Tumor Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: gaemers{at}nki.nl

Retinoid X receptors (RXRs) are key regulators in retinoid signaling. Knowledge about the effects of 9-cis-retinoic acid (9-cis-RA), the natural ligand for the RXRs, may also provide insight in the functions of RXRs. In this study, the effect of 9-cis-RA on spermatogenesis in vitamin A-deficient (VAD) mice was examined. Administration of 9-cis-RA stimulated the differentiation and subsequent proliferation of the growth-arrested A spermatogonia in the testis of VAD mice. However, compared with all-trans-retinoic acid (ATRA), relatively higher doses of 9-cis-RA were necessary. This could not simply be due to a lower or delayed activity of 9-cis-RA, as simultaneous administration of ATRA and 9-cis-RA did not cause a synergistic effect. Instead, the presence of 9-cis-RA diminished the effect of ATRA by approximately one third.

Studies of in vivo transport and metabolism showed that ATRA and 9-cis-RA, after administration to VAD mice, penetrated the testis equally well. However, 9-cis-RA was metabolized much faster than ATRA, and other metabolites were formed. This may account for the above-described differential effects of ATRA and 9-cis-RA on spermatogenesis.

Similar to ATRA, 9-cis-RA transiently induced the messenger RNA expression of the nuclear RA receptor RARß, suggesting a role for this receptor in the effects of retinoids on the differentiation and proliferation of A spermatogonia. In contrast, the messenger RNA expression of the nuclear retinoid receptors RXR, -ß, and - was not changed significantly by administration of their ligand, 9-cis-RA. Hence, 9-cis-RA does not seem to exert its effect on spermatogenesis through altered expression of the RXRs.

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