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Mfsd14a (Hiat1) gene disruption causes globozoospermia and infertility in male mice
Joanne Doran1, Cara Walters2, Victoria Kyle2
1Takeda Cambridge LtdCambridge, UK.
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.
Insights
Disrupting the Mfsd14a gene in mice causes male sterility due to severe defects in sperm development. This suggests MFSD14A protein is crucial for spermiogenesis and sperm formation.
Area of Science:
- Reproductive biology
- Genetics
- Molecular biology
Background:
- The Mfsd14a gene (previously Hiat1) encodes a transmembrane protein with homology to solute carriers.
- The precise function of the MFSD14A protein remains largely unknown.
- Understanding MFSD14A's role is important for reproductive health and understanding genetic mutations.
Purpose of the Study:
- To investigate the function of the MFSD14A protein in vivo.
- To characterize the reproductive phenotype of mice lacking functional Mfsd14a.
- To elucidate the role of Mfsd14a in spermatogenesis.
Main Methods:
- Generation of Mfsd14a-deficient mice using gene disruption with a LacZ reporter.
- Phenotypic analysis of homozygous mutant mice, including reproductive assessment.
- Histological examination of sperm morphology and spermiogenesis.
- Analysis of Mfsd14a expression using beta-galactosidase staining.
Main Results:
- Mfsd14a knockout mice are viable and healthy, but male mice exhibit sterility.
- Sterility is associated with a 100-fold reduction in sperm count and globozoospermia-like defects.
- Spermiogenesis is severely disrupted, with failures in acrosome formation and sperm head condensation.
- Mfsd14a expression is detected in Sertoli cells, indicating a potential role in solute transport.
Conclusions:
- MFSD14A is essential for normal spermiogenesis and male fertility in mice.
- The protein likely plays a critical role in transporting essential solutes required for sperm development.
- Defects in MFSD14A function may contribute to human infertility conditions like globozoospermia.
