ACTRT2 Protein Loss Causes Male Subfertility and Acrosome Defects in Mice
Researchers generated mice lacking the ACTRT2 protein and found that males exhibited subfertility, acrosomal malformations, reduced fertilization rates, and poor blastocyst quality. ACTRT2 localizes to the perinuclear theca of sperm cells and interacts with multiple structural proteins involved in sperm head architecture. The findings suggest ACTRT2 plays a key role in stabilizing the acroplaxome during sperm development and may be relevant to understanding male infertility in humans.
A new study published on bioRxiv reports that male mice lacking the actin-related protein ACTRT2 display subfertility characterized by acrosomal malformations, reduced fertilization rates, and diminished blastocyst quality. ACTRT2 is normally found in the perinuclear theca (PT), a cytoskeletal structure in the sperm head, and is evolutionarily conserved with the highest sequence similarity concentrated in the canonical actin core domain. Using co-immunoprecipitation, the researchers identified ACTRT2 interactions with several other PT proteins—including ACTRT1, ACTRT3, ACTL7A, ACTL9, PFN3, SPEM2, and CCIN—while no interaction with CYLC1 was detected. Overexpression of ACTRT2 in HEK293T cells altered cell morphology and F-actin distribution, and the actin-regulatory protein CFL1 was found to be enriched in testes from ACTRT2-deficient mice, pointing to a role in modulating actin dynamics. The acrosomal defects were traced to the Cap phase of acrosome biogenesis, an early step in sperm maturation. The authors propose that ACTRT2 acts as a structural stabilizer of the acroplaxome and note partial functional redundancy with the related proteins ACTRT1 and ACTRT3, which show similar phenotypes when deleted. Because ACTRT2 is highly conserved, these findings may have implications for diagnosing or understanding idiopathic male infertility in humans.
What's missing
The study is a preprint and has not yet undergone peer review, so findings should be interpreted with caution. The research is conducted entirely in mice, and it remains unknown whether ACTRT2 loss-of-function variants are associated with male infertility in humans. The degree of functional redundancy among ACTRT1, ACTRT2, and ACTRT3 is not fully resolved, and the precise molecular mechanism by which ACTRT2 modulates actin dynamics in the acroplaxome remains to be elucidated. The study does not address whether the subfertility phenotype is fully penetrant or variable across genetic backgrounds.
What different sources said
- bioRxivCenter
Loss of perinuclear theca protein ACTRT2 causes subfertility and acrosome destabilization in mice
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