Cited by 145Sexual Differentiation and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesSperm and Testicular Function

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Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model

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Notini, A J, Davey, R A, McManus, J F, Bate, K L, Zajac, J D·2005·Journal of Molecular Endocrinology

DOI 10.1677/jme.1.01884

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Abstract

Androgens mediate their effects in target cells via the androgen receptor (AR), which acts predominantly as a ligand-dependent transcription factor. In addition, androgens induce rapid activation of second messenger signal transduction cascades, and this is thought to occur via non-genomic mechanisms. We have used the Cre/loxP system to generate an AR knockout (ARKO) mouse targeting exon 3, which encodes the second zinc finger of the DNA-binding domain. To generate universal ARKO mice, floxed AR mice were mated with CMV-Cre mice, which express Cre recombinase ubiquitously. Deletion of the floxed allele in our mice does not disrupt the reading frame, and has been designed so that the mutant AR can bind ligand but not target genes. ARKO males displayed a complete androgen insensitivity phenotype, with female external genitalia and a reduction in body weight compared with wild-type males (P < 0.001). Testes of ARKO males were smaller than control males (P < 0.0001) and were located intra-abdominally. We have demonstrated that genotypically XY mice lacking the second zinc finger of the AR have a female phenotype, and we conclude that the genomic actions of the AR (mediated by DNA binding) are indispensable for normal male sexual differentiation.

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Authors: Notini, A. J., Davey, R. A., McManus, J. F., Bate, K. L., & Zajac, J. D.
Affiliations: The University of Melbourne (AU)
ORCID: Davey, R A
Zajac, J D
Venue: Journal of Molecular Endocrinology
Publisher: Bioscientifica
Published: 2005-12-01
Volume: 35
Issue: 3
Pages: 547-555
ISSN: 0952-5041 (ISSN-L)
1479-6813
DOI: 10.1677/jme.1.01884
OpenAlex: W2104537307
Cited by: 145
References: 37
Citations by year: 2025: 2 · 2024: 8 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 12 · 2014: 18 · 2013: 9 · 2012: 10
FWCI: 2.24
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Molecular Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: Eli Lilly and Company
Cass Foundation
Eli Lilly Australia
Medical Research Council
National Health and Medical Research Council
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords: androgen receptor, male sexual differentiation, androgen insensitivity syndrome, DNA-binding domain, Cre-loxP system, second messenger signaling, testicular development, external genitalia, XY females
MeSH terms: Animals, Base Sequence, Binding Sites, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Pregnancy, Receptors, Androgen, Sex Differentiation, Androgen-Insensitivity Syndrome, Zinc Fingers, Genome, DNA, Complementary, Mice, Knockout, Gene Targeting, Mice

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Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model

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