Brain masculinization requires androgen receptor function.
Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal brain masculinization underlying the expression of male-typical behaviors remains unclear because of the conversion of testosterone into estrogen in the brain. Here, we report a null AR mutation in mice generated by the Cre-loxP system. The AR-null mutation in males (AR(L-/Y)) resulted in the ablation of male-typical sexual and aggressive behaviors, whereas female AR-null homozygote (AR(L-/L-)) mice exhibited normal female sexual behaviors. Treatment with nonaromatizable androgen (5alpha-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in AR(L-/Y) mice. Impaired male-typical behaviors in ERalpha(-/-) mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in AR(L-/L-) mice. Perinatal DHT treatment of females led to adult females sensitive to both 17beta-estradiol and DHT in the induction of male-typical behaviors. However, this female brain masculinization was abolished by AR inactivation. Our results suggested that perinatal brain masculinization requires AR function and that expression of male-typical behaviors in adults is mediated by both AR-dependent and -independent androgen signaling.
Sato
Takashi
T
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Matsumoto
Takahiro
T
Kawano
Hirotaka
H
Watanabe
Tomoyuki
T
Uematsu
Yoshikatsu
Y
Sekine
Keisuke
K
Fukuda
Toru
T
Aihara
Ken-ichi
K
Krust
Andrée
A
Yamada
Takashi
T
Nakamichi
Yuko
Y
Yamamoto
Yoko
Y
Nakamura
Takashi
T
Yoshimura
Kimihiro
K
Yoshizawa
Tatsuya
T
Metzger
Daniel
D
Chambon
Pierre
P
Kato
Shigeaki
S
D059002:Androgen Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D011247:Pregnancy; D011944:Receptors, Androgen / Q000502:physiology*
D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse