Infertility is a significant global issue, affecting both the physical and emotional well-being of those impacted. Genetic mutations influencing early embryonic development, egg cell maturation, and fertilization have been identified as key contributors to infertility. One of the most studied causes of early embryonic infertility is mutations in genes related to the subcortical maternal complex (SCMC), a group of proteins crucial for embryo formation.
SCMC maintains the egg’s cytoplasmic structure and supports proper embryo development by recruiting necessary proteins. The transducin-like enhancer of split 6 (TLE6) is one of the most important proteins in this complex. Without TLE6, the structure of SCMC is compromised, leading to failure in cell division after the two-cell stage of embryo development. This results in embryo fragmentation and death. While research has shown that TLE6 plays a significant role in female infertility, its effects on male fertility have not been well explored.
To address this gap, Kousuke Kazama, a Research Associate at Kanazawa Medical University in Japan, along with Dr. Hirofumi Nishizono and Ms. Yuki Miyagoshi, investigated the impact of TLE6 deficiency on male fertility using a mouse model. Their findings were published in Frontiers in Cell and Developmental Biology on October 24, 2024.
Kazama explained, “We generated Tle6 hetero knockout mice to investigate the effects of Tle6 deficiency in male mice. We used the CRISPR-Cas9 genome-editing system to create these mice.” The team then mated Tle6-deficient and wild-type (WT) male mice with WT females. They found no significant difference in mating behavior or the number of offspring between Tle6-deficient and WT mice. Additionally, embryos derived from the sperm of Tle6-deficient males developed at a similar rate to those from WT males.
The researchers then explored why the genetic traits of Tle6-deficient males were not passed on to the next generation. They hypothesized that reduced sperm count and motility could be factors. Upon analyzing the testes and sperm of Tle6-deficient mice, they found that although the structure of the testes remained intact, sperm count was significantly lower, and sperm motility was notably reduced. About 57% of the sperm had abnormal head structures, with 7% having double heads. Elevated testosterone levels were also observed in these mice.
Further investigation using immunofluorescence staining revealed that TLE6 protein in sperm from deficient mice was localized in the sperm midpiece, overlapping with mitochondria, which produce energy. This suggests TLE6 may play a role in energy production for sperm. Gene expression related to fertilization, sperm motility, and sperm structure in the testes of Tle6-deficient mice also showed increased levels.
The study’s findings underline the potential role of TLE6 in male infertility. Kazama noted, “The role of TLE6 in sperm development may differ between humans and mice. More research is needed to understand how TLE6 deficiency leads to sperm abnormalities and its relevance to human infertility.”
In conclusion, this study advances our understanding of male infertility and could guide future research and the development of new reproductive technologies.
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