Brain masculinization requires androgen receptor function

Takashi Sato, Takahiro Matsumoto, Hirotaka Kawano, Tomoyuki Watanabe, Yoshikatsu Uematsu, Keisuke Sekine, Toru Fukuda, Ken Ichi Aihara, Andrée Krust, Takashi Yamada, Yuko Nakamichi, Yoko Yamamoto, Takashi Nakamura, Kimihiro Yoshimura, Tatsuya Yoshizawa, Daniel Metzger, Pierre Chambon, Shigeaki Kato

Research output: Contribution to journalArticlepeer-review

240 Citations (Scopus)


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 (ARL-/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 (5α-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in ARL-/Y mice. Impaired male-typical behaviors in ERα-/- mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in ARL-/L- mice. Perinatal DHT treatment of females led to adult females sensitive to both 17β-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.

Original languageEnglish
Pages (from-to)1673-1678
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
Publication statusPublished - 2004 Feb 10
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General


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