A role for selective androgen response elements in the development of the epididymis and the androgen control of the 5 <i>α</i> reductase II gene

Abstract

The androgen receptor (AR) recognizes two types of DNA elements that are dimers of 5′‐AGAACA‐3′‐like hexamers, either organized as inverted or direct repeats. We developed a mouse model [(specificity affecting AR knock‐in (SPARKI)] in which the AR DNA‐binding domain was mutated such that it lost binding to direct repeats but not to inverted elements. The impaired fertility of the male SPARKI mice correlates with the reduced motility of the spermatozoa, a characteristic that is developed during transit through the epididymis. Comparative transcriptome analyses revealed that the expression of 39 genes is changed in SPARKI epididymis. Remarkably, the expression of the steroid 5 α ‐reductase type II (Srd5 α 2) gene, which metabolizes testosterone into the more potent dihydrotestosterone, is reduced 4‐fold in SPARKI vs. wild type. The comparison of the SPARKI phenotype with that of Srd5α2 ‐knockout mice shows, however, that the reduced Srd5 α 2 expression cannot explain all defects of the SPARKI epididymis. Moreover, we describe three new selective androgen response elements (AREs), which control the androgen responsiveness of the Srd5α2 gene. We conclude that the SPARKI model can be considered a knockout model for AR functioning via selective AREs and that this has a dramatic effect on sperm maturation in the epididymis.—Kerkhofs, S., Dubois, V., De Gendt, K., Helsen, C., Clinckemalie, L., Spans, L., Schuit, F., Boonen, S., Vanderschueren, D., Saunders, P. T. K., Verhoeven, G., Claessens, F. A role for selective androgen response elements in the development of the epididymis and the androgen control of the 5 α reductase II gene. FASEB J. 26, 4360–4372 (2012). www.fasebj.org