Loss of KIAA1210 leads to increased pyroptotic cell death in mouse spermatogenesis

Intercellular bridge (ICB), ectoplasmic specialization (ES), and blood-testis barrier (BTB) are essential cell-cell junctions for normal spermatogenesis. KIAA1210, which contains several functional domains, has various localizations in the ICB, ES, BTB, acrosome, and XY body. To elucidate the function of KIAA1210 and the functions and relationships of these structures, a KIAA1210 knockout (KO) mouse was generated. In the KO testis, the BTB barrier was depleted, the frequency of pyroptosis increased dramatically, and there was a decrease in total offspring due to delayed acquisition of fertility because of sperm depletion. Interestingly, pyroptosis also occurrs more frequently than apoptosis and parthanatos in wild-type testis, suggesting pyroptosis is a significant quality management system in the normal testis. Pyroptotic cell death occurred more frequently in KIAA1210 KO pachytene spermatocytes, where accidental cell death is likely to occur during homologous recombination. Mosaic mice, which had a mixture of KIAA1210 KO and wild-type cells, had a very severe phenotype, compared to the significantly milder phenotype in KIAA1210 KO mice. DEAD-Box RNA helicase 3 X-linked (DDX3X), which is the upstream factor of pyroptosis and manages cell death and survival, forms a complex with KIAA1210. DDX3X is more strongly localized in the XY body of the pachytene spermatocyte and elongating spermatid in KIAA1210 KO testes compared to WT testes, and might function to replace KIAA1210. Also, the accumulated dead germ cells included destroyed ICBs. This suggests that the chain of germ cells connected via the ICB share the same fate to ensure the integrity of the gamete.