Sertoli cells require TDP-43 to support spermatogenesis†

Area of Science:

• Reproductive Biology
• Molecular Biology
• Cell Biology

Background:

• TAR DNA binding protein of 43 kD (TDP-43) is crucial for gene regulation and is implicated in male reproductive health.
• Aberrant TDP-43 expression is observed in the sperm of infertile men, highlighting its potential role in spermatogenesis.
• Sertoli cells are vital for spermatogenesis, providing essential support to germ cells.

Purpose of the Study:

• To investigate the specific role of TDP-43 within Sertoli cells during spermatogenesis.
• To determine the consequences of TDP-43 deficiency in Sertoli cells on male reproductive function and testicular histology.

Main Methods:

• Conditional knockout (cKO) of TDP-43 in mouse Sertoli cells.
• Assessment of testis weight, sperm count, and testicular histology.
• Biotin tracer assay to evaluate blood-testis barrier (BTB) integrity.
• Analysis of junction protein expression (connexin-43, N-cadherin).
• Oil Red O staining for lipid droplet assessment.
• Quantitative reverse transcription PCR (qRT-PCR) for gene expression analysis.

Main Results:

• Sertoli cell-specific TDP-43 cKO mice exhibited reduced testis weight and low sperm counts, indicating male subfertility.
• Histological analysis revealed germ cell loss, vacuole formation, and spermatid sloughing, suggesting impaired Sertoli cell-germ cell interactions.
• The blood-testis barrier (BTB) integrity was compromised in cKO mice, with disrupted junction proteins.
• Impaired lipid droplet metabolism and altered gene expression related to Sertoli cell junctions and phagocytosis were observed.

Conclusions:

• TDP-43 is indispensable for Sertoli cell function, including germ cell attachment and blood-testis barrier maintenance.
• Sertoli cell phagocytic function is dependent on TDP-43.
• These findings underscore the critical role of TDP-43 in ensuring successful spermatogenesis and maintaining male fertility.