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Hua Mei Reproductive Physiology Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

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Cara Walters Reproductive Physiology Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

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Richard Carter Reproductive Physiology Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

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William H Colledge Reproductive Physiology Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

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Mice with mutations in the kisspeptin signaling pathway (Kiss1−/− or Gpr54−/−) have low gonadotrophic hormone levels, small testes, and impaired spermatogenesis. Between 2 and 7 months of age, however, the testes of the mutant mice increase in weight and in Gpr54−/− mice, the number of seminiferous tubules containing spermatids/spermatozoa increases from 17 to 78%. In contrast, the Kiss1−/− mice have a less severe defect in spermatogenesis and larger testes than Gpr54−/− mice at both 2 and 7 months of age. The reason for the improved spermatogenesis was investigated. Plasma testosterone and FSH levels did not increase with age in the mutant mice and remained much lower than in wild-type (WT) mice. In contrast, intratesticular testosterone levels were similar between mutant and WT mice. These data indicate that age-related spermatogenesis can be completed under conditions of low plasma testosterone and FSH and that intratesticular testosterone may contribute to this process. In addition, however, when the Gpr54−/− mice were fed a phytoestrogen-free diet, they showed no age-related increase in testes weight or improved spermatogenesis. Thus, both genetic and environmental factors are involved in the improved spermatogenesis in the mutant mice as they age although the mice still remain infertile. These data show that the possible impact of dietary phytoestrogens should be taken into account when studying the phenotype of mutant mice with defects in the reproductive axis.

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Tiffany van der Meer Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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W-Y Iris Chan Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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Luis S Palazon Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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Conrad Nieduszynski Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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Martin Murphy Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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Joelle Sobczak-Thépot Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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Mark Carrington Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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William H Colledge Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and INSERM U370, Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France

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In higher eukaryotes, the cyclins constitute a family of proteins involved in progression through the cell cycle. The cyclin A1 gene (Ccna1) is expressed during meiosis and is required for spermatogenesis. Targeted disruption of the Ccna1 gene with a LacZ reporter gene has allowed us to study the expression pattern of this gene in more detail. We have confirmed expression in mouse pre-meiotic spermatocytes and also detected expression in the accessory olfactory bulb, hippocampus and amygdala of the adult brain. We have also found that the amount of cyclin A1 protein influences the fertility of male mice and its action is modulated by genetic background. On an outbred genetic background (129S6/SvEv × MF1), Ccna1 tm1Col −/− animals are sterile due to spermatogenic arrest prior to the first meiotic division while Ccna1 tm1Col +/− mice show reduced sperm production and fertility. This is even more pronounced on an inbred genetic background (129S6/SvEv) where Ccna1 tm1Col +/− male mice are sterile due to a severe reduction in the total number of sperm.

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