Spermiogenesis and exchange of basic nuclear proteins are impaired in malegerm cells lacking Camk4

Ca2+/calmodulin-dependent protein kinase IV (Camk4; also known as CaMKIV), a multifunctional serine/threonine protein kinase with limited tissue distr ibution, has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells(1-6). In the mouse testis, however, Camk4 is ex pressed in spermatids and associated with chromatin and nuclear matrix.(7) Elongating spermatids are not transcriptionally active(8), raising the poss ibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, we have generated mice with a targete d deletion of the gene Camk4. Male Camk4(-/-) mice are infertile with impai rment of spermiogenesis in late elongating spermatids. The sequential depos ition of sperm basic nuclear proteins on chromatin is disrupted, with a spe cific loss of protamine-2 and prolonged retention of transition protein-2 ( Tnp2) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitr o, implicating a connection between Camk4 signalling and the exchange of ba sic nuclear proteins in mammalian male germ cells. Defects in protamine-2 h ave been identified in sperm of infertile men, suggesting that our results may have clinical implications for the understanding of human male infertil ity.