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Targeting Sperm Tails: A Potential Cure to Male Infertility

Researchers have identified the role of a sperm tail protein in causing male infertility, unveiling a new target for boosting sperm movement, reversing mutations, and curing infertility.

Plaguing more than 20 million men worldwide, male infertility accounts for 50 per cent of all infertility cases in couples. Male infertility refers to the inability of males to impregnate a fertile female and is often associated with a deficiency in semen or poor semen quality. However, recent findings have identified a new possible culprit of male infertility – malformations in the sperm cells, particularly in the tail.

Sperm tails, otherwise known as the flagellum, are responsible for regulating movement to allow the sperm to swim towards an egg during fertilisation. As such, deformations like shortened, irregular, coiled flagella or its lack thereof can lead to acute infertility.

Scientists have reasoned that these flawed tails occur as a result of genetic mutations, particularly mutations affecting the sheath that covers the sperm, the mitochondria that power the sperm to swim, as well as the acrosomal vesicle carrying the enzymes needed to digest the exterior of the egg cell to fertilise it.

Following the tracks of previous research, scientists from Guangzhou Women and Children’s Medical Center led by Drs Na Li and Ling Sun, gathered sperm specimens from infertile men to better understand the underlying mechanisms of male infertility. Analyses of these samples led them to discover one individual who harboured multiple defects affecting his sperm flagella. Further analyses found a mutation in a largely overlooked sperm protein known as Fibrous Sheath-Interacting Protein 2 (FSIP2), a component of the fibrous sheath.

“The fibrous sheath covers the tails of sperm found in humans, mice and other species in which fertilisation occurs within the animal’s body,” explained Li. “It offers the sperm tails flexibility and strength, which is necessary for sperm to swim in the dense and sticky medium of the human body before they meet the egg. Interestingly, animals whose sperm swim through water because fertilization occurs outside of the body, such as fish, either do not have the FSIP2 protein or, at most, a defective version.”

To investigate the functions of the FSIP2 protein, the researchers generated two sets of mice: one in which they reproduced the mutated FSIP2 protein of the human patient, and another in which the mice overproduced the FSIP2 protein.

Their findings showed that mice with mutated FSIP2 become infertile. A closer inspection at their semen revealed there being fewer live sperm, with over 50 per cent of them incapable of swimming forward despite their functional flagella. In contrast, the mice that overexpressed the FSIP2 protein were not only fertile but also had much longer sperm cells, over seven times the average length. These sperm cells were found to be able to swim faster and demonstrated a higher capacity to fertilise egg cells.

The stark difference observed by altering just this one protein led scientists to further examine the composition of the sperm to explain why the sperm flagella were so greatly affected by changes in the FSIP2 protein.

The team discovered that by mutating the FSIP2 protein, proteins needed to encapsulate the sperm, generate mitochondrial power, and form the acrosomal vesicle were produced at lower quantities, hence compromising sperm function. In contrast, sperm overexpressing FSIP2 proteins can induce greater production of sperm tail proteins, specifically those of the fibrous sheath, which support swimming.

These novel findings are expected to pave the way for treatments for male infertility. The scientists hope to explore drugs that can restore sperm movement or better yet, rectifying these debilitating mutations, bringing new hopes for infertile men to become fathers. [APBN]

Source: Fang et al. (2021). Hypomorphic and hypermorphic mouse models of Fsip2 indicate its dosage-dependent roles in sperm tail and acrosome formation. Development, 148(11), dev199216