Study reveals role of TLE6 in male sperm development

Study reveals role of TLE6 in male sperm development

Infertility is a major global challenge associated with physiological and psychological impacts. Genetic mutations that affect early embryonic development, egg maturation, and fertilization have recently been investigated as causes of infertility. One of the most studied causes of early embryonic infertility are mutations in genes related to the subcortical maternal complex (SCMC).

SCMC is involved in the development and cleavage of the embryo by maintaining the structure of the egg's cytoplasm and recruiting proteins that support proper embryo formation. SCMC is composed of several proteins, of which the transducin-like enhancer of split 6 (TLE6) is the most important member. In the absence of TLE6, the structural integrity of SCMC is compromised and cell division in the embryo fails after the two-cell stage, leading to embryo fragmentation and death. There is ample evidence for the role of TLE6 in female infertility, but its role in male germ cells remains unexplored.

To fill this gap, Mr. Kousuke Kazama, a research fellow from the Research Support Center of the Medical Research Institute of Kanazawa Medical University, Japan, along with Dr. Hirofumi Nishizono and Ms. Yuki Miyagoshi, also from Kanazawa Medical University, understand the implicationsTle6Gene deficiency affects male fertility using theTle6defective mouse model. They developed a novelTle6Gene hetero-knockout model of a male mouse using a technique called CRISPR-Cas9 that allows gene editing. Their results were published in Volume 12 ofLimits of cell and developmental biologyon October 24, 2024.

“We generated Tle6 hetero-knockout mice to examine the effects of Tle6 deficiency in male mice. We performed genome editing of the embryos using the CRISPR-Cas9 system and electroporation to generate the Tle6 hetero-knockout mice.explains Kazama, explaining the main methodology of the study. To investigate whetherTle6Deficiency leads to irregular mating behavior,Tle6-deficient and male wild-type (WT) mice were mated with female WT mice. The frequency of mating and the number of offspring did not differTle6-deficient and WT mice. In addition, embryos come from the sperm ofTle6-deficient male mice showed similar developmental rates to those derived from WT male mouse sperm.

The question of whyTle6Deficiency-related traits were not passed on to the next generation, prompting researchers to further investigate the gene's role in sperm function. Kazama elaborates: “We hypothesized that the difficulty in transferring genetic traits from Tle6-deficient male mice might be due to reduced sperm count and motility.” To test this hypothesis, they analyzed the testes and sperm ofTle6-deficient male mice. While the structure of the testicles was not affected by thisTle6When there was a deficiency, they found a significant reduction in sperm count and a significant decrease in the number of motile sperm. In addition, 57% of spermTle6-deficient mice had abnormal head structure and 7% were double-headed. The researchers suspected that these mice had disrupted hormone levels and, as a result, found increased levels of testosterone (an important sex hormone).Tle6male hetero-knockout mice.

Visualization of sperm from WT andTle6Knockout mice using immunofluorescence staining showed that the TLE6 protein was localized to the sperm midpiece in deficient mice. This region overlapped with the location of mitochondria, which are important for energy production, suggesting that TLE6 may play a role in energy production in sperm. Gene expression related to fertilization, sperm motility and sperm structure in the testes ofTle6-deficient mice showed an overall increase.

Taken together, the results of this study highlighted the impact ofTle6Deficiency in male mice and its role in possible male infertility. “The role of TLE6 in sperm development may be different in humans and mice. Therefore, further studies are needed to clarify the mechanisms by which Tle6 deficiency causes sperm abnormalities in Tle6 hetero-knockout mice and to investigate its clinical relevance in humans.“ concludes Kazama.

In conclusion, this study sheds more light on male infertility and paves the way for more advanced research and the development of new assisted reproductive technologies.

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