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      OAZ-t/ OAZ3 Is Essential for Rigid Connection of Sperm Tails to Heads in Mouse

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          Abstract

          Polyamines are known to play important roles in the proliferation and differentiation of many types of cells. Although considerable amounts of polyamines are synthesized and stored in the testes, their roles remain unknown. Ornithine decarboxylase antizymes (OAZs) control the intracellular concentration of polyamines in a feedback manner. OAZ1 and OAZ2 are expressed ubiquitously, whereas OAZ-t/OAZ3 is expressed specifically in germline cells during spermiogenesis. OAZ-t reportedly binds to ornithine decarboxylase (ODC) and inactivates ODC activity. In a prior study, polyamines were capable of inducing a frameshift at the frameshift sequence of OAZ-t mRNA, resulting in the translation of OAZ-t. To investigate the physiological role of OAZ-t, we generated OAZ-t–disrupted mutant mice. Homozygous OAZ-t mutant males were infertile, although the polyamine concentrations of epididymides and testes were normal in these mice, and females were fertile. Sperm were successfully recovered from the epididymides of the mutant mice, but the heads and tails of the sperm cells were easily separated in culture medium during incubation. Results indicated that OAZ-t is essential for the formation of a rigid junction between the head and tail during spermatogenesis. The detached tails and heads were alive, and most of the headless tails showed straight forward movement. Although the tailless sperm failed to acrosome-react, the heads were capable of fertilizing eggs via intracytoplasmic sperm injection. OAZ-t likely plays a key role in haploid germ cell differentiation via the local concentration of polyamines.

          Author Summary

          Polyamines are essential for cell proliferation and differentiation, but their role in these processes is unknown. Ornithine decarboxylase antizymes (OAZs) are enzymes that control the concentration of polyamines in cells. To elucidate the role of one of these enzymes, OAZ-t, in the regulation of polyamine concentration during sperm formation, we generated mutant mice in which the OAZ-t gene was disrupted. When we observed sperm from the mice lacking a functional Oaz-t gene, we found that the sperm heads separated easily from the tails, indicating that OAZ-t is essential for the formation of a rigid junction between the head and tail during sperm development. Many of the headless tails could continue swimming, but they were unable to participate in the signaling processes required for successful fertilization. However, tailless heads could produce healthy pups when injected into unfertilized eggs. Such a phenotype has not been previously found. The mutant mice evoked rare cases of infertile human patients whose sperm behaves in a proper fashion. Our study underscores the importance of research into the processes of spermatogenesis and fertilization.

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          Polyamines.

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            All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility.

            Mammalian spermatozoa become motile at ejaculation, but before they can fertilize the egg, they must acquire more thrust to penetrate the cumulus and zona pellucida. The forceful asymmetric motion of hyperactivated spermatozoa requires Ca2+ entry into the sperm tail by an alkalinization-activated voltage-sensitive Ca2+-selective current (ICatSper). Hyperactivation requires CatSper1 and CatSper2 putative ion channel genes, but the function of two other related genes (CatSper3 and CatSper4) is not known. Here we show that targeted disruption of murine CatSper3 or CatSper4 also abrogated ICatSper, sperm cell hyperactivated motility and male fertility but did not affect spermatogenesis or initial motility. Direct protein interactions among CatSpers, the sperm specificity of these proteins, and loss of ICatSper in each of the four CatSper-/- mice indicate that CatSpers are highly specialized flagellar proteins.
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              Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination.

              Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is the most rapidly turned over mammalian enzyme. We have shown that its degradation is accelerated by ODC antizyme, an inhibitory protein induced by polyamines. This is a new type of enzyme regulation and may be a model for selective protein degradation. Here we report the identification of the protease responsible for ODC degradation. Using a cell-free degradation system, we demonstrate that immunodepletion of proteasomes from cell extracts causes almost complete loss of ATP- and antizyme-dependent degradation of ODC. In addition, purified 26S proteasome complex, but not the 20S proteasome, catalyses ODC degradation in the absence of ubiquitin. These results strongly suggest that the 26S proteasome, widely viewed as specific for ubiquitin-conjugated proteins, is the main enzyme responsible for ODC degradation. The 26S proteasome may therefore have a second role in ubiquitin-independent proteolysis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                November 2009
                November 2009
                6 November 2009
                : 5
                : 11
                : e1000712
                Affiliations
                [1 ]TANAKA Project, Center for Advanced Science and Innovation, Osaka University, Suita, Osaka, Japan
                [2 ]Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
                [3 ]Laboratory of Functional Anatomy, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki, Japan
                [4 ]Department of Bioscience and Biotechnology, Faculty of Bioenvironmental Science, Kyoto Gakuen University, Kameoka, Kyoto, Japan
                [5 ]Department of Hygiene Chemistry, Ohu University School of Pharmaceutical Sciences, Koriyama, Fukushima, Japan
                [6 ]Molecular Biology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki, Japan
                [7 ]Microbiology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki, Japan
                [8 ]Research Collaboration Center on Emerging and Re-emerging Infections, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
                The University of North Carolina at Chapel Hill, United States of America
                Author notes

                Conceived and designed the experiments: HT. Performed the experiments: KT AI SY YY SO KF YO. Analyzed the data: KT MH MW HT. Contributed reagents/materials/analysis tools: MO YN HT. Wrote the paper: HT.

                Article
                09-PLGE-RA-0922R3
                10.1371/journal.pgen.1000712
                2763286
                19893612
                1e4fe9ff-1827-49e6-82cc-699e37516f6e
                Tokuhiro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 2 June 2009
                : 5 October 2009
                Page count
                Pages: 7
                Categories
                Research Article
                Developmental Biology/Germ Cells

                Genetics
                Genetics

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