Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model.
Androgens influence transcription of their target genes through the activation of the androgen receptor (AR) that subsequently interacts with specific DNA motifs in these genes. These DNA motifs, called androgen response elements (AREs), can be classified in two classes: the classical AREs, which are also recognized by the other steroid hormone receptors; and the AR-selective AREs, which display selectivity for the AR. For in vitro interaction with the selective AREs, the androgen receptor DNA-binding domain is dependent on specific residues in its second zinc-finger. To evaluate the physiological relevance of these selective elements, we generated a germ-line knockin mouse model, termed SPARKI (SPecificity-affecting AR KnockIn), in which the second zinc-finger of the AR was replaced with that of the glucocorticoid receptor, resulting in a chimeric protein that retains its ability to bind classical AREs but is unable to bind selective AREs. The reproductive organs of SPARKI males are smaller compared with wild-type animals, and they are also subfertile. Intriguingly, however, they do not display any anabolic phenotype. The expression of two testis-specific, androgen-responsive genes is differentially affected by the SPARKI mutation, which is correlated with the involvement of different types of response elements in their androgen responsiveness. In this report, we present the first in vivo evidence of the existence of two functionally different types of AREs and demonstrate that AR-regulated gene expression can be targeted based on this distinction.
Schauwaers
Kris
K
Molecular Endocrinology Laboratory, Department of Molecular Cell Biology, Catholic University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
De Gendt
Karel
K
Saunders
Philippa T K
PT
Atanassova
Nina
N
Haelens
Annemie
A
Callewaert
Leen
L
Moehren
Udo
U
Swinnen
Johannes V
JV
Verhoeven
Guido
G
Verrijdt
Guy
G
Claessens
Frank
F
D000595:Amino Acid Sequence; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D002452:Cell Count; D005260:Female; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D023421:Models, Animal; D008969:Molecular Sequence Data; D010641:Phenotype; D011485:Protein Binding; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D012098:Reproduction / Q000502:physiology*; D020218:Response Elements / Q000235:genetics*; D013737:Testis / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D016335:Zinc Fingers
D000728:Androgens; D018398:Homeodomain Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; C498048:Rhox5 protein, mouse; D014157:Transcription Factors; C477828:eppin protein, mouse