Molecular Mechanisms of Sperm Function and Fertility

Spermatozoa development and function depend on a cascade of molecular events that begin with the differentiation of germ cells and culminate in the orchestration of motility, capacitation, acrosome reaction and sperm–egg fusion. Spermiogenesis remodels nuclear architecture through protamine incorporation and histone replacement, while cytoskeletal and fibrous sheath proteins assemble to form a flagellum capable of vigorous, energy-efficient motility. Posttranscriptional and posttranslational regulation—including selective polyadenylation and reversible phosphorylation—fine-tunes protein abundance and activity in transcriptionally silent spermatozoa. Redox balance, mediated by antioxidant enzymes and reversible oxidative modifications, further modulates capacitation and signalling pathways. Central to these processes are scaffold proteins such as A-kinase anchoring proteins (AKAPs), which integrate cyclic AMP–protein kinase A and protein kinase C–ERK1/2 signals to coordinate capacitation and the acrosome reaction. Insights into motor proteins and dynein regulation illuminate the assembly and maintenance of flagellar ultrastructure, contributing to our understanding of male fertility and its disorders worldwide.

Research from Nature Portfolio

Recent studies have revealed that a family of non-canonical poly(A) polymerases is essential for proper gametogenesis in mammals. Loss of specific enzymes disrupts the polyadenylation of mRNAs encoding endoplasmic reticulum-targeted proteins, leading to chromosomal aberrations in oocytes and sterility in males due to failed spermatogenesis. This work highlights the importance of cytoplasmic mRNA regulation in sperm development. In parallel, characterisation of a scaffold protein in human sperm has shown that its phosphorylation by ERK1/2 serves as a molecular switch between the cyclic AMP–PKA and PKC–ERK1/2 pathways. This crosstalk governs capacitation dynamics and acrosome responsiveness, demonstrating how spatially organised kinase signalling underlies key functional transitions in spermatozoa.

Molecular Mechanisms of Sperm Function and Fertility publication trend

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

Technical terms

Capacitation: A series of biochemical and physiological changes that render sperm competent to undergo the acrosome reaction and fertilise an oocyte.

Acrosome reaction: The exocytotic release of enzymes from the sperm’s acrosomal vesicle, enabling penetration of the zona pellucida.

Polyadenylation: The addition of a poly(A) tail to mRNA transcripts, which influences their stability and translational efficiency in germ cells.

Posttranslational modification: Chemical alterations to proteins, such as phosphorylation or oxidation, that regulate protein activity, localisation and interactions.

A-kinase anchoring protein (AKAP): A scaffold protein that binds protein kinase A and other kinases, organising them into signalling complexes in sperm.

Spermiogenesis: The final phase of spermatogenesis during which round spermatids transform into mature, motile spermatozoa.

References

1. TENT5-mediated polyadenylation of mRNAs encoding secreted proteins is essential for gametogenesis in mice. Nature Communications (2024).
2. New insights into posttranslational modifications of proteins during bull sperm capacitation. Cell Communication and Signaling (2023).
3. STK33 Phosphorylates Fibrous Sheath Protein AKAP3/4 to Regulate Sperm Flagella Assembly in Spermiogenesis. Molecular & Cellular Proteomics (2023).
4. Actl7b-deficiency leads to mislocalization of LC8 type dynein light chains and disruption of murine spermatogenesis. Development (2023).
5. A-Kinase Anchoring Protein 4 (AKAP4) is an ERK1/2 substrate and a switch molecule between cAMP/PKA and PKC/ERK1/2 in human spermatozoa. Scientific Reports (2016).