Gene linked to infertility in male mice

Research from the Department of Neuroscience at the University of Cambridge, Cambridge, United Kingdom shows how the disruption of a gene in development, is linked to abnomal sperm and infertility in male mice.

The gene known as Hiat1, now called Mfsd14a, codes for a protein similar to one found in humans. It affects a factor found in cell membranes which eases substances across the cell membrane and into the nucleus. This work is published in the journal Reproduction.

To study its function, mutant mice were generated with an abnormal Mfsd14a gene. Although the mutant mice were healthy, all males were sterile. They had a complete lack of sperm in their vas deferens. Although their levels of testosterone were normal, as was their ability to copulate, the few sperm they produced had round heads — similar to those found in humans with globozoospermia, a disorder causing male infertility.

Globozoospermia begins at the formation of the round spermatids or immature male sex cells, and goes on to become severely disruptive to mature sperm. It produces sperm with an acrosome incorrectly shaped to cover the sperm head and still assist in penetration of the outer egg membrane — very important to fertilization. The sperm head, enclosed within the acrosome, has not condensed efficiently, staying somewhat round in shape. Other abnormalities include a mismatch of mitochondrial allignment in the connecting sheath, located in the mid piece between head and tail. The tail may also be less able to produce the whiplike movement needed to propel the sperm through the vaginal canal, up through the uterus and into the fallopian tubes to reach and fertilize the egg. Image Credit: Wikipedia

Mfsd14a may be failing to transport soluable substances out of the bloodstream and into somatic cells located in the tubules of the testis. These cells are precursor cells on their way to becomming sertoli cells, which will develop into sperm. The factors from the bloodstream are needed to condense and compact materials within the sertoli cell nucleus in order for each to mature into, in humans, an oval sperm head.

Identifying specific genes at fault in development, and knowing the processes affected sperm generation in particular. Such knowledge helps in diagnosing the specific causes of male infertility. This type of basic research will also help direct future research into treatment, or possibly even repair, for various infertility conditions.

Abstract
The Mfsd14a gene, previously called Hiat1, encodes a transmembrane protein of unknown function with homology to the solute carrier protein family. To study the function of the MFSD14A protein, mutant mice (Mus musculus, strain 129S6Sv/Ev) were generated with the Mfsd14a gene disrupted with a LacZ reporter gene. Homozygous mutant mice are viable and healthy, but males are sterile due to a 100-fold reduction in the number of spermatozoa in the vas deferens. Male mice have adequate levels of testosterone and show normal copulatory behaviour. The few spermatozoa that are formed show rounded head defects similar to those found in humans with globozoospermia. Spermatogenesis proceeds normally up to the round spermatid stage, but the subsequent structural changes associated with spermiogenesis are severely disrupted with failure of acrosome formation, sperm head condensation and mitochondrial localization to the mid-piece of the sperm. Staining for β-galactosidase activity as a surrogate for Mfsd14a expression indicates expression in Sertoli cells, suggesting that MFSD14A may transport a solute from the bloodstream that is required for spermiogenesis.
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In order for sperm to penetrate an egg, the acrosome must be tough and somewhat pointed.
Image Credit: public domain