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ARRDC5: a newly identified regulator of spermatogenesis

Written by Charlotte Harrison, Science Writer

A study by researchers at Washington State University indicates that a molecule called ARRDC5 (α-arrestin molecule arrestin-domain containing 5) is key to regulating the production of sperm in mammals.

The findings, published in Nature Communications, improve our understanding of spermatogenesis in mammals and suggest that ARRDC5 is a potential target for male contraceptives.

Important genes

Prior to the study, the core molecular mechanisms essential for sperm formation were not well understood. To find germ-cell genes involved in sperm production across mammalian species, the authors generated a single-cell transcriptome profile of testicular tissue from mice, cattle and pigs.

The candidate genes were then refined through bioinformatic analyses to those with germ cell-enriched expression that had not been previously linked with spermatogenesis in the literature.

From this list of genes, Arrdc5 appeared as a prime candidate. The researchers showed that Arrdc5 mRNA was present in testes of mice, pigs, cattle, and importantly, expression was enriched in human testicular tissue.

Biological function

Subsequently, the researchers generated knock-out mice to determine the biological function of Arrdc5. Phenotyping analysis showed that ARRDC5 deficiency led to male-specific sterility, as evidenced by reduced sperm counts and motility, and abnormal sperm morphology. Male sterility was the only phenotype of the mice, and knockout females had normal fertility.  

Further work showed that sperm from Arrdc5-deficient mice did not undergo the final maturation step and could not achieve natural fertilization.

Possible therapeutic target

Overall, the findings show that the arrestin molecule ARRDC5 regulates mammalian spermatogenesis.

The authors note that “Although the exact molecular function of ARRDC5 in male germ

cells remains to be elucidated, the presumed biological role as an E3 ubiquitin ligase adapter may make it a druggable target for male contraceptive development”.

Indeed, they have filed a provisional patent for developing a male contraceptive based on ARRDC5.