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Updated: Oct 23, 2025
Determination of Reproductive Competence by Confirming Pubertal Onset and Performing a Fertility Assay in Mice and Rats
Published on: October 13, 2018
Male fertility in mice requires classical and nonclassical androgen signaling
Paul S Cooke1, William H Walker2
1Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, USA.
Abstract:
Molecular mechanisms by which androgens signal through the androgen receptor (AR) to maintain male fertility are poorly understood. Transgenic mice were produced expressing mutant ARs that can only (1) alter gene transcription through the classical response pathway (AR-C) or (2) activate kinase signaling cascades via the nonclassical pathway (AR-NC). AR-C is sufficient to produce sperm and fertility. Haploid germ cell production, the blood-testis barrier, and spermatid migration are supported by AR-NC. Gene expression essential for chromosome synapsis during meiosis requires AR-C. We identify targets of androgen signaling required for male fertility and provide a mechanistic explanation for meiotic germ cell arrest in the absence of androgen signaling. Prostate differentiation occurs with AR-C alone, but full development requires synergistic nonclassical signaling. Both AR signaling pathways are necessary for normal male reproductive tract development and function, validating our mouse models for studies of AR functions in other target tissues.
Insights
Androgen receptor (AR) signaling is crucial for male fertility. Distinct pathways, classical (AR-C) and nonclassical (AR-NC), control sperm production, meiosis, and reproductive tract development.
Area of Science:
- Reproductive Biology
- Molecular Endocrinology
- Genetics
Background:
- The precise molecular mechanisms by which androgens regulate male fertility via the androgen receptor (AR) remain incompletely understood.
- Androgen signaling is essential for male reproductive tract development and function, but the distinct roles of its various pathways are not fully elucidated.
Purpose of the Study:
- To elucidate the specific roles of the classical (AR-C) and nonclassical (AR-NC) androgen receptor signaling pathways in male fertility.
- To identify key androgen signaling targets essential for spermatogenesis, meiosis, and reproductive tract development.
Main Methods:
- Generation of transgenic mice expressing mutant androgen receptors selectively activating either the classical (AR-C) or nonclassical (AR-NC) signaling pathways.
- Phenotypic analysis of reproductive organs, sperm production, meiotic progression, and gene expression in mutant mice.
Main Results:
- AR-C signaling alone is sufficient for sperm production and fertility.
- AR-NC signaling is essential for haploid germ cell production, maintaining the blood-testis barrier, and spermatid migration.
- AR-C is required for gene expression critical for chromosome synapsis during meiosis.
- Both AR-C and AR-NC pathways are necessary for complete prostate development and overall male reproductive tract function.
Conclusions:
- Androgen receptor classical and nonclassical signaling pathways play distinct but complementary roles in male fertility.
- AR-C governs transcriptional regulation for sperm production and meiosis, while AR-NC controls germ cell development and tissue integrity.
- These findings provide a mechanistic explanation for male infertility due to disrupted androgen signaling and validate novel mouse models for studying AR functions.
