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Differential Functions of the Aurora-B and Aurora-C Kinases in Mammalian Spermatogenesis

Departments of Animal Science and Pharmacology and Therapeutics (S.K.), McGill University, Montreal, Canada H3G 1Y6; Fondazione Santa Lucia Istituto e Cura a Carattere Scientifico (C.C.), 00179 Rome, Italy; Department of Physiology, Institute of Biomedicine (N.K.), University of Turku, FI-20520 Turku, Finland; Department of Pharmacology (J.H., P.S.-C.), School of Medicine, University of California, Irvine, Irvine, California 92697; Center for Genomics and Bioinformatics (C.H.), Karolinska Institutet, S-171 77 Stockholm, Sweden; Department of Human Physiology and Pharmacology (L.M.), University of Rome "La Sapienza," 00185 Rome, Italy; and Department of Target Discovery (J.A.G., M.v.D.), NV Organon, 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Paolo Sassone-Corsi, Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, California 92697. E-mail: psc{at}uci.edu.

The Aurora kinases are cell cycle-regulatory serine-threonine kinases that have been implicated in the function of the centrosomes, kinetechores, chromosome dynamics, and cytokinesis. In comparison with other tissues, there are high levels of expression of Aurora-B and -C in testis. What their respective roles in mammalian spermatogenesis are is an open question. Here we describe the expression and distribution patterns of the three kinases in mouse testis using in situ hybridization and immunohistochemistry. Importantly, the localization of Aurora-B is tightly regulated during spermatogenesis, whereas Aurora-C expression appears to be testis specific. To address the function of Aurora-B in spermatogenesis, we have generated transgenic mice using a pachytene-stage-specific promoter driving the expression of either wild-type Aurora-B or an inactive form of the kinase. Expression of the inactive Aurora-B results in abnormal spermatocytes, increased apoptosis, spermatogenic arrest, and subfertility defects. The function of Aurora-C may also be targeted in the Aurora-B transgenic mutants. To address the function of Aurora-C in testis, we generated Aurora-C knockout mice by homologous recombination. Remarkably, Aurora-C null mice were viable, yet the males had compromised fertility. Aurora-C mutant sperm display abnormalities that included heterogenous chromatin condensation, loose acrosomes, and blunted heads. These findings indicate that Aurora-B and Aurora-C serve specialized functions in mammalian spermatogenesis.

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