The nuclear import factor importin α4 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 IMP alpha proteins is highly dynamic. Present predominantly from the spermatocyte stage onwards, IMP alpha 4 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 IMP alpha 4 in vivo for the first time using a novel transgenic mouse model in which we overexpress an IMP alpha 4-EGFP fusion protein from the protamine 1 promoter to recapitulate endogenous testicular germ cell IMP alpha 4 expression in spermatids. IMP alpha 4 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 IMP alpha 4 in protecting against oxidative stress, haploid germ cells from IMP alpha 4 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 IMP alpha 4 in stress responses specifically within haploid male germline cells, with implications for male fertility and genetic integrity. (C) 2013 Elsevier B.V. All rights reserved.