Premature ovarian failure in androgen receptor-deficient mice.
Premature ovarian failure (POF) syndrome, an early decline of ovarian function in women, is frequently associated with X chromosome abnormalities ranging from various Xq deletions to complete loss of one of the X chromosomes. However, the genetic locus responsible for the POF remains unknown, and no candidate gene has been identified. Using the Cre/LoxP system, we have disrupted the mouse X chromosome androgen receptor (Ar) gene. Female AR(-/-) mice appeared normal but developed the POF phenotype with aberrant ovarian gene expression. Eight-week-old female AR(-/-) mice are fertile, but they have lower follicle numbers and impaired mammary development, and they produce only half of the normal number of pups per litter. Forty-week-old AR(-/-) mice are infertile because of complete loss of follicles. Genome-wide microarray analysis of mRNA from AR(-/-) ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by AR. Our findings suggest that AR function is required for normal female reproduction, particularly folliculogenesis, and that AR is a potential therapeutic target in POF syndrome.
Shiina
Hiroko
H
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Matsumoto
Takahiro
T
Sato
Takashi
T
Igarashi
Katsuhide
K
Miyamoto
Junko
J
Takemasa
Sayuri
S
Sakari
Matomo
M
Takada
Ichiro
I
Nakamura
Takashi
T
Metzger
Daniel
D
Chambon
Pierre
P
Kanno
Jun
J
Yoshikawa
Hiroyuki
H
Kato
Shigeaki
S
D000818:Animals; D015153:Blotting, Western; D005260:Female; D007150:Immunohistochemistry; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D006080:Ovarian Follicle / Q000033:anatomy & histology / Q000254:growth & development*; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011944:Receptors, Androgen / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014960:X Chromosome / Q000235:genetics*
D011944:Receptors, Androgen; D008156:Luciferases