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The Effect of a Sertoli Cell-Selective Knockout of the Androgen Receptor on Testicular Gene Expression in Prepubertal Mice

Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven (E.D., K.D.G., J.V.S., G.V.), and Microarray Facility, Flanders Interuniversity for Biotechnology (P.V.H.), Gasthuisberg, B-3000 Leuven, Belgium; Department of Electrical Engineering, Faculty of Engineering (J.A., K.E., K.M.), and Center for Microbial and Plant Genetics, Faculty of Applied Bioscience and Engineering (K.M.), Catholic University of Leuven, B-3001 Heverlee, Belgium; and Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, Queen’s Medical Research Institute, University of Edinburgh (K.A.L.T., R.M.S., P.T.K.S.), Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Guido Verhoeven, Laboratory for Experimental Medicine and Endocrinology, Onderwijs en Navorsing, Gasthuisberg, Herestraat 49 bus 902, B-3000 Leuven, Belgium. E-mail: guido.verhoeven{at}med.kuleuven.be.

To unravel the molecular mechanisms mediating the effects of androgens on spermatogenesis, testicular gene expression was compared in mice with Sertoli cell-selective androgen receptor knockout (SCARKO) and littermate controls on postnatal d 10. Microarray analysis identified 692 genes with significant differences in expression. Of these, 28 appeared to be down-regulated and 12 up-regulated at least 2-fold in SCARKOs compared with controls. For nine of the more than 2-fold down-regulated genes, androgen regulation was confirmed by treatment of wild-type mice with an antiandrogen (flutamide). Some of them were previously described to be androgen regulated or essential for spermatogenesis. Serine-type protease inhibitors were markedly overrepresented in this down-regulated subgroup. A time study (d 8–20), followed by cluster analysis, allowed identification of distinct expression patterns of differentially expressed genes. Three genes with a pattern closely resembling that of Pem, a prototypical androgen-regulated gene expressed in Sertoli cells, were selected for confirmation by quantitative RT-PCR and additional analysis. The data confirm that the SCARKO model allows identification of novel androgen-regulated genes in the testis. Moreover, they suggest that protease inhibitors and other proteins related to tubular restructuring and cell junction dynamics may be controlled in part by androgens.

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