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Developmental Biology - Sperm

Protein Defect Leaves Sperm Chasing Their Tails

How a defective protein causes sperm to swim in circles...

With more and more couples seeking assistance to conceive, the steps required for fertilization are being put under the microscope to identify factors that could enhance fertility. In a study published in the journal PNAS, a team led by researchers from Osaka University describe an exciting breakthrough that may aid in future fertility treatments.

When it comes down to it, sperm have only one job: to fertilize the egg. To do this though, they must first make their way to the fallopian tube, propelled by long tails called flagella.
When they near their destination, sperm become turbo-charged in a process known as capacitation, allowing them to race towards the egg. This enhanced motility is triggered by an influx of calcium ions into the flagellum.

While researchers have known for some time that an electrical signal-sensing protein called VSP is expressed in sperm of many animal species, this protein's actual physiological role was unknown.
"Determining the physiological role of VSP was the main aim of our study. To do this, we generated a VSP-deficient mouse line so that we could examine VSP-deficient sperm from these animals."

Takafumi Kawai PhD, Graduate School of Medicine, Osaka University, Japan; Graduate School of Frontier Bioscience, Osaka University, Japan.

Researchers first noticed that VSP-deficient sperm had a greatly reduced ability to fertilize eggs in vitro. Closer inspection revealed the sperm were swimming around in circles during capacitation, meaning fewer sperm actually made it to their destination. Defective motility suggested a problem with the flagellum, prompting researchers to examine these structures in more detail.
"Surprisingly, in normal sperm, a lipid molecule called PIP2 is concentrated near the top of the flagellum, closer to the head. In the VSP-deficient sperm, PIP2 was both more abundant and more widely dispersed throughout the flagellum. We also recorded much higher concentrations of calcium ions in the VSP-deficient sperm."

Takafumi Kawai PhD.

The findings suggest VSP plays a major role in ion channel regulation, which ultimately affects motility. Researchers propose VSP is responsible for the polarized distribution of PIP2 in the flagellum. PIP2 activates potassium ion channels, which indirectly causes a localized influx of calcium ions, thus enhancing their motility.

In VSP-deficient sperm, the dispersed PIP2 causes excessive calcium ion influx which decreases the flexibility of the flagellum, affecting their motility.

The discovery of VSP-based regulation of sperm motility has significant implications for male fertility. Adds Kawai: "We predict our findings will lead to the development of fertility treatments enhancing sperm motility, increasing chances for fertilization,"

Voltage-sensing phosphatase (VSP) is a unique protein that consists of both the voltage-sensor domain and phosphoinositide phosphatase domain. In contrast with intensive studies on its molecular mechanisms, its physiological role has not been clear. Here, we report that VSP plays critical roles in mouse sperm motility. We found that VSP generates a polarized distribution of PtdIns(4,5)P2 in the sperm flagellum, which is critical for regulation of ion channel activity and calcium influx in sperm function. This provides a mode of regulation of ion channel activity by biased distribution of PtdIns(4,5)P2.

The voltage-sensing phosphatase (VSP) is a unique protein that shows voltage-dependent phosphoinositide phosphatase activity. Here we report that VSP is activated in mice sperm flagellum and generates a unique subcellular distribution pattern of PtdIns(4,5)P2. Sperm from VSP-/- mice show more Ca2+ influx upon capacitation than VSP+/- mice and abnormal circular motion. VSP-deficient sperm showed enhanced activity of Slo3, a PtdIns(4,5)P2-sensitive K+ channel, which selectively localizes to the principal piece of the flagellum and indirectly enhances Ca2+ influx. Most interestingly, freeze-fracture electron microscopy analysis indicates that normal sperm have much less PtdIns(4,5)P2 in the principal piece than in the midpiece of the flagellum, and this polarized PtdIns(4,5)P2 distribution disappeared in VSP-deficient sperm. Thus, VSP appears to optimize PtdIns(4,5)P2 distribution of the principal piece. These results imply that flagellar PtdIns(4,5)P2 distribution plays important roles in ion channel regulation as well as sperm motility.

Takafumi Kawai, Haruhiko Miyata, Hiroki Nakanishi, Souhei Sakata, Shin Morioka, Junko Sasaki, View ORCID ProfileMasahiko Watanabe, Kenji Sakimura, View ORCID ProfileToyoshi Fujimoto, Takehiko Sasaki, View ORCID ProfileMasahito Ikawa, and Yasushi Okamura.

The authors declare no competing interest.

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Dec 6 2019   Fetal Timeline   Maternal Timeline   News 

Sperm sense an "electrical signal," resulting in changes in motility. Intracellular enzyme activity
is also upregulated in response to that electrical signal. CREDIT Osaka University.
Movie of sperm swimming in circles.

Phospholid by Wikipedia