IP6K1 is essential for chromatoid body formation and temporal regulation of TNP2 and PRM2 expression in mouse spermatids

Abstract

Inositol hexakisphosphate kinases (IP6Ks) are enzymes that synthesise the inositol pyrophosphate 5-IP7, which is known to regulate several physiological processes. Deletion of IP6K1, but not other IP6K isoforms, causes sterility in male mice. Here, we present a detailed investigation of the specific function of IP6K1 in spermatogenesis. Within the mouse testis, IP6K1 is expressed at high levels in late stage pachytene spermatocytes and in round spermatids. We found IP6K1 to be a novel component of the chromatoid body, a cytoplasmic granule in round spermatids composed of RNA and RNA binding proteins, and noted that this structure is absent in Ip6k1−/-round spermatids. Furthermore, juvenile spermatids from Ip6k1−/- mice display premature expression of the transition protein TNP2 and the protamine PRM2 due to translational derepression. The aberrant localisation of these key sperm-specific chromatin components, together with the persistence of somatic histones, results in abnormal spermatid elongation, failure to complete spermatid differentiation, and azoospermia in these mice. Our study thus identifies IP6K1 as an indispensable factor in the temporal regulation of male germ cell differentiation.