sirt1 deficiency attenuates spermatogenesis and germ cell functionsirt1缺乏变弱精子发生和生殖细胞功能.pdf

Sirt1 Deficiency Attenuates Spermatogenesis and Germ Cell Function 1,2 1 1 1 1,2 Matthew Coussens , John G. Maresh , Ryuzo Yanagimachi , Gregg Maeda , Richard Allsopp * 1John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, 2 Institute for Biogenesis Research, University of Hawaii, Honolulu, Hawaii Abstract In mammals, Sirt1, a member of the sirtuin family of proteins, functions as a nicotinamide adenine dinucleotide-dependent protein deactylase, and has important physiological roles, including the regulation of glucose metabolism, cell survival, and mitochondrial respiration. The initial investigations of Sirt1 deficient mice have revealed a phenotype that includes a reduced lifespan, small size, and an increased frequency of abnormal sperm. We have now performed a detailed analysis of the molecular and functional effects of Sirt1 deficiency in the germ line of Sirt1 knock-out (2/ 2) mice. We find that Sirt1 deficiency markedly attenuates spermatogenesis, but not oogenesis. Numbers of mature sperm and spermatogenic precursors, as early as d15.5 of development, are significantly reduced (,2-10-fold less; P#0.004) in numbers in Sirt12/ 2 mice, whereas Sirt1 deficiency did not effect the efficiency oocyte production following superovulation of female mice. Furthermore, the proportion of mature sperm with elevated DNA damage (,7.5% of total epididymal sperm; P = 0.02) was significantly increased in adult Sirt12/ 2 males. Analysis of global gene expression by microarray analysis in Sirt1 deficient testis revealed dysregulated expression of 85 genes, which were enriched (P,0.05) for genes involved in spermatogenesis and protein sumoylation. To assess the function of S