Inositol hexakisphosphate kinase 1 is essential for cell junction integrity in the mouse seminiferous epithelium

• Published in: Biochimica et biophysica acta. Molecular cell research 2024-01, Vol.1871 (1), p.119596-119596, Article 119596
• Main Authors: Bhat, Sameer Ahmed, Malla, Aushaq Bashir, Oddi, Vineesha, Sen, Jayraj, Bhandari, Rashna
• Format: Article
• Language: English
• Subjects: Actin cytoskeleton; Blood-testis barrier; Cell junctions; IP6K; Spermatogenesis
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2023.119596

Inositol hexakisphosphate kinases (IP6Ks) are enzymes that catalyse the synthesis of the inositol pyrophosphate 5-IP7 which is involved in the regulation of many physiological processes in mammals. The IP6K paralog IP6K1 is expressed at high levels in the mammalian testis, and its deletion leads to sterility in male mice. Here, we show that the loss of IP6K1 in mice causes a delay in the first wave of spermatogenesis. Testes from juvenile Ip6k1 knockout mice show downregulation of transcripts that are involved in cell adhesion and formation of the testis-specific inter-Sertoli cell impermeable junction complex known as the blood-testis barrier (BTB). We demonstrate that loss of IP6K1 in the mouse testis causes BTB disruption associated with transcriptional misregulation of the tight junction protein claudin 3, and subcellular mislocalization of the gap junction protein connexin 43. In addition to BTB disruption, we also observe a loss of germ cell adhesion in the seminiferous epithelium of Ip6k1 knockout mice, ultimately resulting in premature sloughing of round spermatids into the epididymis. Mechanistically, we show that loss of IP6K1 in the testis enhances cofilin dephosphorylation in conjunction with increased AKT/ERK and integrin signalling, resulting in destabilization of the actin-based cytoskeleton in Sertoli cells and germ cell loss. •IP6K1 knockout mice show a delay in the first wave of spermatogenesis.•Loss of IP6K1 downregulates cell adhesion related genes in the testes.•IP6K1 maintains the integrity of the blood-testis barrier.•Loss of IP6K1 activates integrin and growth factor receptor signalling.•IP6K1 knockout testes show disrupted actin cytoskeleton; cofilin dephosphorylation.