Protein behind streamlined sperm opens door for male contraceptives

Once more the holy grail of male contraceptives! It may also help with the genetic diagnosis of male infertility.

Here is another, recent of my blog posts on this subject.

"... 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. ...
“We found that spermatozoa from the mice with disrupted TSKS failed to develop a streamlined form, resulting in male infertility.” ..."

From the significance and abstract:

"Significance

Spermatozoa have a streamlined shape to swim through the female reproductive tract to fertilize oocytes. However, little is known about the process of elimination of spermatid cytoplasm. When we created Tsks-null mice, the knockout mice cannot generate two types of nuage, reticulated body (RB) and chromatoid body remnant (CR), and are sterile with abnormal elimination of spermatid cytoplasm. Due to the absence of RB and CR, Tsks knockout spermatozoa have excess residual cytoplasm because the cytoplasmic contents cannot be eliminated from spermatid cytoplasm. These results suggest that TSKS-derived nuage are essential for spermatozoa to be streamlined. This study contributes to our understanding of spermiation, genetic diagnosis of idiopathic male infertility, and treatment of patients with infertility.

Abstract

Spermatozoa have a streamlined shape to swim through the oviduct to fertilize oocytes. To become svelte spermatozoa, spermatid cytoplasm must be eliminated in several steps including sperm release, which is part of spermiation. Although this process has been well observed, the molecular mechanisms that underlie it remain unclear. In male germ cells, there are membraneless organelles called nuage, which are observed by electron microscopy in various forms of dense material. Reticulated body (RB) and chromatoid body remnant (CR) are two types of nuage in spermatids, but the functions of both are unknown. Using CRISPR/Cas9 technology, we deleted the entire coding sequence of testis-specific serine kinase substrate (TSKS) in mice and demonstrate that TSKS is essential for male fertility through the formation of both RB and CR, prominent sites of TSKS localization. Due to the lack of TSKS-derived nuage (TDN), the cytoplasmic contents cannot be eliminated from spermatid cytoplasm in Tsks knockout mice, resulting in excess residual cytoplasm with an abundance of cytoplasmic materials and inducing an apoptotic response. In addition, ectopic expression of TSKS in cells results in formation of amorphous nuage-like structures; dephosphorylation of TSKS helps to induce nuage, while phosphorylation of TSKS blocks the formation. Our results indicate that TSKS and TDN are essential for spermiation and male fertility by eliminating cytoplasmic contents from the spermatid cytoplasm."

Protein behind streamlined sperm opens door for male contraceptives

TSKS localizes to nuage in spermatids and regulates cytoplasmic elimination during spermiation (open access)

Fig 1 TSKS-deleted male mice are sterile