Hypomorphic and hypermorphic mouse models of Fibrous Sheath Interacting Protein 2 (FSIP2) indicate its dose-dependent roles in sperm tail and acrosome formation.
New Hope for Male Infertility Depends on Flagellar Protein
Male infertility affects more than 20 million men worldwide. Often, male infertility is caused by defects in the sperm's tail (flagellum).
A flagellum is a lash-like appendage that allows the sperm to swim upstream toward the fallopian tubes on its mission to fertilize an egg.
Severely infertile males can develop multiple sperm abnormalities, including short, irregular, coiled, or even absent flagella, which prevents the sperm from swimming and reaching the target.
In humans, several genetic mutations lead to the deformation of sperm or malformed sperm, including those that affect the fibrous sheath that covers the sperm; the mitochondria which provide it with the ability to swim upstream toward the fallopian tubes to fertilize an egg.
Mutations can also cause a defect in the small sac known as the acrosomal vesicle, which releases enzymes that allow a successful sperm to break down the outer lining of the egg cell to fertilize it.
In a new study, researchers have identified a mutation in a relatively unknown sperm protein, FSIP2, that is a component of the sperm’s fibrous sheath in an infertile man with multiple defects in sperm flagella.
To understand more about the causes of male infertility, researchers in a new study published in the journal "Development" collected sperm samples from infertile men and identified an individual with multiple defects affecting the flagella.
Through genetic analysis, they found a mutation in the sperm protein. The mutation, called FSIP2 (Fibrous Sheath Interacting Protein 2) was not known at all.
The fibrous sheath is the part that covers the tails of sperm found in humans, mice, and other species in which fertilization takes place inside the animal's body. This sheath provides flexibility and strength to the sperm's tail, which is necessary for the sperm to swim through the dense, sticky medium of the human body before meeting the egg.
Interestingly, animals whose sperm swims in water because fertilization takes place outside the body, such as fish, either do not have FSIP2 or contain a defective copy of the gene.
To study the function of FSIP2, the scientific team that prepared this study generated two groups of mice. The first group included mice that had a defective copy of the gene, while the mice of the second group had an active copy of the gene that made the levels of protein secretion high.
The researchers found that mice with a defective mutation in the FSIP2 protein became infertile, as the semen contained fewer live sperm and more than 50 percent of them could not swim forward, and the mice that overproduced FSIP2 remained fertile. Compared to normal mice, they had about 7 times longer sperm, which could swim faster and be better able to fertilize an egg.
To understand the reasons for these changes in the sperm flagellum, the researchers looked at spermatogenesis and the composition of the sperm. They found that the sperm of mice with the FSIP2 mutation contained fewer proteins that make up the sheath surrounding the sperm, and the sperm of mice that overproduced FSIP2 made more sperm tail proteins, especially in the fibrous sheath, which may allow the sperm to swim more easily through the body.
The team's findings offer hope that scientists can begin to develop treatments for infertility either by finding drugs that restore sperm motility or even by finding ways to correct the debilitating mutation that's causing the problems in the first place.