Cited by 303Sexual Differentiation and DisordersNeuroendocrine regulation and behaviorGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

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Brain masculinization requires androgen receptor function

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Sato, Takashi, Matsumoto, Takahiro, Kawano, Hirotaka, Watanabe, Tomoyuki, Uematsu, Yoshikatsu, Sekine, Keisuke, Fukuda, Toru, Aihara, Ken-ichi, Krust, Andrée, Yamada, Takashi, Nakamichi, Yuko, Yamamoto, Yoko, Nakamura, Takashi, Yoshimura, Kimihiro, Yoshizawa, Tatsuya, Metzger, Daniel, Chambon, Pierre, Kato, Shigeaki·2004·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0305303101PMC PMC341816

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Abstract

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 (5α-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 ER α -/- 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 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.

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Authors: Sato, T., Matsumoto, T., Kawano, H., Watanabe, T., Uematsu, Y., Sekine, K., Fukuda, T., Aihara, K.-I., Krust, A., Yamada, T., Nakamichi, Y., Yamamoto, Y., Nakamura, T., Yoshimura, K., Yoshizawa, T., Metzger, D., Chambon, P., & Kato, S.
Affiliations: Centre National de la Recherche Scientifique (FR)
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Orthopedic Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National...
ORCID: Sato, Takashi
Kawano, Hirotaka
Watanabe, Tomoyuki
Sekine, Keisuke
Aihara, Ken-ichi
Yamada, Takashi
Nakamichi, Yuko
Yamamoto, Yoko
Nakamura, Takashi
Yoshizawa, Tatsuya
Metzger, Daniel
Chambon, Pierre
Kato, Shigeaki
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2004-01-27
Volume: 101
Issue: 6
Pages: 1673-1678
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0305303101
PMC: PMC341816
OpenAlex: W2002653885
Cited by: 303
References: 25
Citations by year: 2026: 5 · 2025: 6 · 2024: 15 · 2023: 9 · 2022: 13 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 15 · 2016: 8 · 2015: 17 · 2014: 21 · 2013: 25 · 2012: 14
FWCI: 5.21
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords: brain masculinization, androgen receptor, aromatase, estrogen receptor alpha, sexual behavior, aggression, dihydrotestosterone, androgen signaling, sex differences in brain development
MeSH terms: Animals, Behavior, Animal, Brain, Female, Male, Mice, Inbred C57BL, Pregnancy, Receptors, Androgen, Gene Expression Regulation, Enzymologic, Nitric Oxide Synthase, Mice, Nitric Oxide Synthase Type I, Androgen Receptor Antagonists

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Brain masculinization requires androgen receptor function

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