Protein behind streamlined sperm opens door for male contraceptives

 

Swimmers who wore Speedo’s controversial LZR Racer suit at the 2008 Beijing Olympics broke 23 out of the 25 world records broken, proving that being more streamlined has advantages. A new study out of Japan has shown that the same theory applies to sperm.

Spermatozoa must travel through the female reproductive tract to fertilize an egg. With hundreds of millions of them vying for a single egg, having an advantage over the competition is essential. It’s a sperm’s streamlined design that allows for its rapid movement, thereby providing that advantage.

It’s well known that an immature sperm (spermatids) is surrounded by cytoplasm, a gelatinous liquid. To become more streamlined, that cytoplasm must be discarded before mature spermatozoa are released from the Sertoli cells that created them, in a process called spermiation. Although the process of shedding spermatid cytoplasm has been observed in previous studies, the molecular mechanisms underlying it remain unclear.

Inside a germ cell, which develops into either an egg or a sperm, there exist tiny membrane-less structures rich in RNA called nuage. Nuage are thought to be essential to germ cell specialization and interact with a protein-coding gene involved in sperm production, testis-specific serine kinase substrate (TSKS).

Researchers from Osaka University in Japan examined how using the CRISPR/Cas9 system to delete the entire coding sequence of TSKS in mice affects the shape of the spermatozoa they produce.

“Using genome editing technology, we developed a mouse model in which TSKS has been disrupted,” said Keisuke Shimada, co-lead author of the study. “We found that spermatozoa from the mice with disrupted TSKS failed to develop a streamlined form, resulting in male infertility.”

The researchers discovered that disrupting TSKS meant spermatids did not produce two specific kinds of nuage, reticulated body (RB) and chromatid body remnant (CR). Without RB and CR, the mice's spermatozoa could not properly shed their cytoplasm, ultimately resulting in cell death (apoptosis). The study demonstrates that TSKS is essential for the formation of RB and CR nuage.

“Our results showed that generation of RB and CR nuage is dependent on TSKS,” said Soojin Park, the study’s co-lead author. “TSKS is required for sperm to eliminate cytoplasm and adapt a streamlined, tadpole shape.”

While the study highlights the link between TSKS and nuage, the molecular mechanisms underlying the cytoplasm elimination process remain a mystery that will require further study.

“Even though there are many missing links between TSKS function and the spermiation process, it may be possible to understand these mechanisms if we acquire more knowledge about TSKS and related proteins,” the researchers said.

Regardless, the study’s findings are relevant to diagnosing and treating infertility and hold potential for developing male contraceptives.

“Our studies can contribute to our understanding of spermiation, genetic diagnosis of idiopathic male infertility, and treatments of patients with infertility,” the researchers said. “[T]he findings may lead to the development of male contraceptives if we could find compounds that inhibit spermiation.”

The study was published in the journal Proceedings of the National Academy of Sciences.

Source: Osaka University/New Atlas