Title: SPARKI: a mouse model to study the in vivo role of selective androgen response elements
Other Titles: SPARKI: een muismodel voor het bestuderen van de 'in vivo' rol van selectieve androgeen-responsieve elementen
Authors: Schauwaers, Kris; M0120063
Issue Date: 21-Jun-2007
Abstract: Androgens play a crucial role in the development of the male urogenitaltract and external genitalia. They are key effectors in both androgenicand anabolic events, and they are involved in the development of secondary sexual characteristics and in the homeostasis of their target tissues during adulthood. These effects involve interaction of the androgen with the androgen receptor (AR), a member of the family of steroid receptors (SRs). This androgen-AR complex will bind as a dimer to androgen response elements (AREs) on the DNA, eventually affecting the transcription of nearby target genes. Two types of AREs have been described in vitro : the classical AREs, which are also recognized by other SRs like the glucocorticoid receptor (GR), and the AR-selective AREs, which are not recognized by the GR. It is known that the second zinc-finger of the DNA-binding domain (DBD) of the AR is crucial for interaction with selective AREs. We therefore postulate that the AR has different subsets of targetgenes: those that are mainly regulated by classical AREs, those that are dependent on selective AREs, and those that are driven by both types of motifs The aim of this study was to investigate the physiological role of selective AREs, and the identification of genes and gene networks that are regulated via selective AREs. For this reason, we developed a transgenic mouse model, called ‘SP ecificity-affecting AR K nock-I n’ or SPARKI. In these mice, the second zinc-finger of the AR-DBD is replaced with the second zinc-finger of the GR. In vitro , this mutation makes the AR no longer capable of binding to selective AREs.SPARKI males display a clear reproductive phenotype. Their reproductiveorgans are on average reduced in weight to 60% of wild-type (WT) and they are subfertile. They have normal testosterone and gonadotropin serum levels, indicating that the observed reproductive defects are not explained by a general androgen resistance. Spermatogenesis is reduced, which might be explained by a decreased number of Sertoli cells and a lowercapacity of these cells to support meiotic and post-meiotic germ cells.In addition, the epididymis is affected, both in morphology and function. Sperm maturation in SPARKI mice seems disturbed, as their spermatozoaare less motile and the sperm tails have more structural abnormalities than WT tails.Molecular analysis of gene expression provided a first proof-of-principle that androgen-regulated genes are differentially affected by the SPARKI mutation. Indeed, the Rhox5 gene expression is strongly reduced in SPARKI testes, while the Eppin gene expression is not affected. The Rhox5 gene promoter was shown to harbour a selective ARE, while the Eppin gene promoter contains a classical ARE.Surprisingly, no effects on androgen-dependent anabolic parameters are seen in SPARKI males. They have normal body weights and fat mass, organsoutside the reproductive system are not affected, bone mineral density is not disturbed, and muscle activity seems normal. These results are the first indication that the SPARKI mutation may have a system-specific effect. It is therefore likely that not only genes can be assigned to a group driven by classical versus selective AREs, but that also the different physiological androgen-dependent programs, like reproduction and anabolism, may be controlled differentially by either class of response elements. In conclusion, the SPARKI model is an interesting tool to evaluate the physiological relevance of selective AREs. These results could be of major importance in the development of more selective androgen receptor modulators (SARMs), which would target only those genes that are driven by either classical or selective AREs. These drugs might maximize thedesired pharmacological effect and minimize unwanted side effects in the treatment of androgen-related pathologies.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Biochemistry Section (Medicine) (-)

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