title: SirT1 is required in the male germ cell for differentiation and fecundity in mice.
abstract: Sirtuins are NAD(+)-dependent deacylases that regulate numerous biological processes in response to the environment. SirT1 is the mammalian ortholog of yeast Sir2, and is involved in many metabolic pathways in somatic tissues. Whole body deletion of SirT1 alters reproductive function in oocytes and the testes, in part caused by defects in central neuro-endocrine control. To study the function of SirT1 specifically in the male germ line, we deleted this sirtuin in male germ cells and found that mutant mice had smaller testes, a delay in differentiation of pre-meiotic germ cells, decreased spermatozoa number, an increased proportion of abnormal spermatozoa and reduced fertility. At the molecular level, mutants do not have the characteristic increase in acetylation of histone H4 at residues K5, K8 and K12 during spermiogenesis and demonstrate corresponding defects in the histone to protamine transition. Our findings thus reveal a germ cell-autonomous role of SirT1 in spermatogenesis.
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Glenn Laboratory for the Science of Aging, Cambridge, MA 02139, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.affiliation: Center for Epigenetics and Metabolism, Department of Biological Chemistry, University of California, Irvine, CA 92697, USA Osaka University, Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Nagamori
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Glenn Laboratory for the Science of Aging, Cambridge, MA 02139, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Williams
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Del Rosario
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Massachusettes Institute of Technology, Department of Biological Engineering, Cambridge, MA 02139, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Bryson
authors.affiliation: W. M. Keck Microscopy Facility Whitehead Institute, Cambridge, MA 02139, USA.
authors.forename: Nicki
authors.initials: N
authors.lastname: Watson
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Massachusettes Institute of Technology, Department of Biological Engineering, Cambridge, MA 02139, USA.
authors.forename: Forest M
authors.initials: FM
authors.lastname: White
authors.affiliation: Center for Epigenetics and Metabolism, Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Glenn Laboratory for the Science of Aging, Cambridge, MA 02139, USA Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA leng@mit.edu.
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002853:Chromatography, Liquid; D005260:Female; D005298:Fertility / Q000235:genetics* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005854:Germ Cells / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational / Q000235:genetics; D056564:Sirtuin 1 / Q000172:deficiency / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics*; D053719:Tandem Mass Spectrometry; D013737:Testis / Q000378:metabolism
chemical_list: D006657:Histones; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Male germ cell; Reproduction; SirT1