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Exploring Independent Effects of Follicle-Stimulating Hormone In Vivo in a Mouse Model
Published on: August 11, 2023
Premature ovarian failure in androgen receptor-deficient mice
Hiroko Shiina1, Takahiro Matsumoto, Takashi Sato
1Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract:
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.
Insights
The androgen receptor (AR) gene is crucial for female reproduction. Disrupting the AR gene in mice leads to premature ovarian failure (POF) and impaired folliculogenesis, suggesting AR as a therapeutic target for POF.
Area of Science:
- Reproductive Biology
- Genetics
- Endocrinology
Background:
- Premature ovarian failure (POF) is linked to X chromosome abnormalities, but the specific genetic causes remain unclear.
- The androgen receptor (AR) gene, located on the X chromosome, plays a role in reproductive functions.
Purpose of the Study:
- To investigate the role of the androgen receptor (AR) gene in female reproduction and its potential link to premature ovarian failure (POF).
Main Methods:
- Utilized the Cre/LoxP system to disrupt the androgen receptor (Ar) gene in female mice, creating AR(-/-) mice.
- Assessed reproductive phenotypes, ovarian function, mammary development, and performed genome-wide microarray analysis of ovarian gene expression.
Main Results:
- Female AR(-/-) mice exhibited premature ovarian failure (POF) with reduced follicle numbers and impaired folliculogenesis by 40 weeks of age.
- Microarray analysis revealed that AR regulates key genes involved in folliculogenesis.
- Younger AR(-/-) mice showed reduced fertility and impaired mammary development.
Conclusions:
- Androgen receptor (AR) function is essential for normal female reproduction, specifically for ovarian folliculogenesis.
- The study identifies AR as a potential therapeutic target for treating premature ovarian failure (POF).
