Molecular Mechanisms of Male Fertility in Murine Models

The male reproductive capacity in mice rests on intricately coordinated molecular pathways at each stage of sperm production, maturation and function. Within the testis, mitotic proliferation of spermatogonia, meiotic division of spermatocytes and morphological remodelling during spermiogenesis generate haploid spermatozoa. Post-translational processing in the endoplasmic reticulum and Golgi apparatus ensures correct folding and formation of disulfide bonds in key structural and signalling proteins. During transit through the epididymis, lumicrine signals derived from the testis drive epithelial differentiation and regional secretion of proteins required for membrane remodelling, motility acquisition and fertilisation competence. Mitochondrial biogenesis and sheath assembly in the sperm midpiece provide the energy necessary for flagellar motion, while precise organisation of the annulus and axoneme underlies rapid, directed swimming. Genetic ablation of individual testis-enriched genes has revealed both indispensable regulators of fertility and families of redundant factors, highlighting functional networks that underpin sperm maturation, oviductal migration and sperm–egg interaction. Understanding these pathways in murine models not only sheds light on the fundamental biology of reproduction but also informs approaches to treat male infertility and to develop non-hormonal contraceptives.

Research from Nature Portfolio

Recent studies have revealed novel components of lumicrine signalling that are critical for epididymal differentiation and sperm maturation. One such protein acts as an essential cofactor in a complex with a testis-derived ligand, translocating from the testis to the epididymal lumen to trigger epithelial remodelling. Mice lacking this cofactor exhibit defective epididymal segmentation, impaired sperm maturation and male sterility, which can be rescued by targeted re-expression in germ cells, underscoring the physiological importance of testis-to-epididymis communication for fertility.

Molecular Mechanisms of Male Fertility in Murine Models publication trend

The graph below shows the total number of articles in molecular mechanisms of male fertility in murine models across all publications each year (not limited to Nature Index journals).

Technical terms

Lumicrine signalling: A testis-derived secreted factor pathway that travels through the luminal fluid to the epididymis, promoting epithelial differentiation. Epididymis: The duct system through which sperm undergo biochemical and morphological maturation before storage and ejaculation. Spermiogenesis: The terminal phase of sperm development in which round spermatids elongate, condense chromatin and form specialised structures. Mitochondrial sheath: The spiral arrangement of mitochondria around the sperm midpiece that generates ATP for flagellar beating. Protein disulfide isomerase (PDI): An endoplasmic reticulum enzyme that catalyses formation, breakage and rearrangement of disulfide bonds in nascent proteins. Acrosome: A specialised, enzyme-filled vesicle capping the sperm nucleus essential for penetration of the oocyte’s zona pellucida.

References

1. A small secreted protein NICOL regulates lumicrine-mediated sperm maturation and male fertility. Nature Communications (2023).
2. MORN2 regulates the morphology and energy metabolism of mitochondria and is required for male fertility in mice. Journal of Translational Medicine (2024).
3. Spem2, a novel testis-enriched gene, is required for spermiogenesis and fertilization in mice. Cellular and Molecular Life Sciences (2024).
4. Protein disulfide isomerase is essential for spermatogenesis in mice. JCI Insight (2024).
5. TTC6-Mediated Stabilization of the Flagellum Annulus Ensures the Rapid and Directed Motion of Sperm. Cells (2023).