Title: Physiological role of selective androgen response elements
Other Titles: Fysiologische functie van selectieve androgeen responsieve elementen
Authors: Kerkhofs, Stefanie; M0323191
Issue Date: 29-Nov-2011
Abstract: Androgens are male steroid hormones that play a crucial role in masculinization of the fetus, development of internal and external reproductive organs and in development of male secondary sexual characteristics. Androgens have an effect on reproductive organs as well as on anabolic parameters like body composition, bone parameters and muscle characteristics. The major circulating androgen is testosterone which is converted in some target tissues/cells to the more potent metabolite 5α-dihydrotestosterone by steroid 5α-reductase enzymes. Androgens interact with the androgen receptor (AR) and induce homodimeric binding to either classical androgen response elements (AREs), organized as inverted repeats, or to selective AREs organized as partial direct repeats of the 5’-AGAACA-3’ consensus sequence. The AR is a member of the steroid receptor family which contains also the glucocorticoid (GR), mineralocorticoid (MR) and progesterone receptor (PR). Classical AREs are recognized by all members of the steroid receptor family, except the estrogen receptor, while selective AREs are only recognized by the AR and the PR. A mouse model (SPARKI, Specificity affecting AR Knock-In) was developed in which the exon encoding the second Zn-finger of the AR was swapped with the corresponding exon of the glucocorticoid receptor. This mutated AR has strongly reduced affinities for selective AREs but not for classical AREs (Schauwaers et al., 2007). SPARKI males are subfertile, have smaller reproductive organs and reduced spermatogenesis. However, no anabolic parameters seem to be affected by this mutation. The subfertility seems in large part due to defects at the level of the epididymis. The epididymis consists of a single, highly convoluted tubule that links the efferent ducts with the vas deferens and is anatomically divided into an initial segment, caput, corpus and cauda. As spermatozoa transit through the epididymis, they develop forward motility and they acquire the capacity to fertilize. SPARKI spermatozoa, taken from the cauda epididymis, are less motile and show more structural abnormalities compared to WT. Comparative transcriptome analyses of WT and SPARKI epidiymides revealed a number of down-regulated genes in SPARKI epididymis, possibly involved in sperm maturation. Orchidectomy showed clear androgen-responsiveness of these genes in WT epididymis, which is strongly reduced in SPARKI males. One of the regulated genes is carbonic anhydrase 4 which is involved in the early activation of sperm motility by bicarbonate in the epididymis (Wandernoth et al., 2010). Mice with a knock-out of this gene have less motile spermatozoa comparable with the reduced motility observed in SPARKI spermatozoa. Another down-regulated gene is the steroid 5α-reductase type II gene (Srd5a2), which metabolises testosterone into the more potent dihydrotestosterone. Using electrophoretic mobility shift assays and transient transfection studies, we were able to describe novel selective and classical AREs in intronic regions of this gene. Importantly, those genes that are down-regulated in the SPARKI epididymis are unaffected in epididymides of Srd5a2 knock-out mice, suggesting that the SPARKI phenotype is not secondary to the reduced expression of Srd5a2. We therefore conclude that the SPARKI epididymal phenotype is caused by the lost responsiveness of a specific set of genes of which the androgen regulation is controlled by selective AREs. Schauwaers K, De Gendt K, Saunders PT, Atanassova N, Haelens A, Callewaert L, Moehren U, Swinnen JV, Verhoeven G, Verrijdt G & Claessens F 2007 Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model. Proc Natl Acad Sci U S A 104 4961-4966.Wandernoth PM, Raubuch M, Mannowetz N, Becker HM, Deitmer JW, Sly WS & Wennemuth G 2010 Role of carbonic anhydrase IV in the bicarbonate-mediated activation of murine and human sperm. PLoS One 5 e15061.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Molecular Endocrinology
Biochemistry Section (Medicine) (-)
Faculty of Medicine - miscellaneous
Clinical and Experimental Endocrinology

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