Abnormal spermatogenesis and reduced fertility in transition nuclear protein l-deficient mice

Transition nuclear proteins (TPs), the major proteins found in chromatin of condensing spermatids. are believed to be important for histone displaceme nt and chromatin condensation during mammalian spermatogenesis. We generate d mice lacking the major TP, TP1, by targeted deletion of the Tnp1 gene in mouse embryonic stem cells. Surprisingly, testis weights and sperm producti on were normal in the mutant mice, and only subtle abnormalities were obser ved in sperm morphology, Electron microscopy revealed large rod-like struct ures in the chromatin of mutant step 13 spermatids. in contrast to the fine chromatin fibrils observed in wild type. Steps 12-13 spermatid nuclei from the testis of Tnp1-null mice contained, in place of TP1, elevated levels o f TP2 and some protamine 2 (P2) precursor. Most of the precursor was proces sed to mature PZ. but high levels of incompletely processed forms remained in epididymal spermatozoa. Sperm motility was reduced severely, and approxi mate to 60% of Tnp1-null males were infertile. We concluded that TP1 is not essential for histone displacement or chromatin condensation. The absence of TP1 may partially be compensated for by TP2 and P2 precursor, but this d ysregulation of nucleoprotein replacement results in an abnormal pattern of chromatin condensation and in reduced fertility.