The nuclear import factor importin a4 can protect against oxidative stress

The importin (IMP) superfamily of nuclear transport proteins is essential to key developmental pathways, including in the murine testis where expression of the 6 distinct IMPalpha proteins is highly dynamic. Present predominantly from the spermatocyte stage onwards, IMPalpha4 is unique in showing a striking nuclear localization, a property we previously found to be linked to maintenance of pluripotency in embryonic stem cells and to the cellular stress response in cultured cells. Here we examine the role of IMPalpha4 in vivo for the first time using a novel transgenic mouse model in which we overexpress an IMPalpha4-EGFP fusion protein from the protamine 1 promoter to recapitulate endogenous testicular germ cell IMPalpha4 expression in spermatids. IMPalpha4 overexpression did not affect overall fertility, testis morphology/weight or spermatogenic progression under normal conditions, but conferred significantly (>30 ) increased resistance to oxidative stress specifically in the spermatid subpopulation expressing the transgene. Consistent with a cell-specific role for IMPalpha4 in protecting against oxidative stress, haploid germ cells from IMPalpha4 null mice were significantly (c. 30 ) less resistant to oxidative stress than wild type controls. These results from two unique and complementary mouse models demonstrate a novel protective role for IMPalpha4 in stress responses specifically within haploid male germline cells, with implications for male fertility and genetic integrity.