title: Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain.
abstract: Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis.
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Victoria A
authors: VA
authors: Rafalski
authors: Peggy P
authors: PP
authors: Ho
authors: Jamie O
authors: JO
authors: Brett
authors: Duygu
authors: D
authors: Ucar
authors: Jason C
authors: JC
authors: Dugas
authors: Elizabeth A
authors: EA
authors: Pollina
authors: Lionel M L
authors: LM
authors: Chow
authors: Adiljan
authors: A
authors: Ibrahim
authors: Suzanne J
authors: SJ
authors: Baker
authors: Ben A
authors: BA
authors: Barres
authors: Lawrence
authors: L
authors: Steinman
authors: Anne
authors: A
authors: Brunet
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002490:Central Nervous System / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
references: J Neurosci. 2012 Jan 4;32(1):124-32
references: 22219275
references: Sci Transl Med. 2012 Aug 1;4(145):145ra105
references: 22855462
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: J Exp Med. 1949 Sep;90(3):213-24
references: 18137295
references: Eur J Immunol. 1995 Jul;25(7):1951-9
references: 7621871
references: J Neurosci. 2006 Jul 26;26(30):7907-18
references: 16870736
references: Eur J Neurosci. 1999 Dec;11(12):4357-66
references: 10594662
references: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6685-90
references: 19346468
references: Nat Cell Biol. 2008 Apr;10(4):385-94
references: 18344989
references: Clin Cancer Res. 2004 Aug 1;10(15):5271-81
references: 15297431
references: PLoS One. 2011;6(5):e20600
references: 21655185
references: Cell Stem Cell. 2009 Nov 6;5(5):527-39
references: 19896443
references: Nat Med. 2011 Dec 18;18(1):159-65
references: 22179316
references: J Neurosci. 1998 Jun 15;18(12):4627-36
references: 9614237
references: Genes Dev. 2009 Dec 15;23(24):2812-7
references: 20008932
references: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10032-7
references: 10944195
references: Cancer Cell. 2010 Dec 14;18(6):669-82
references: 21156288
references: Cancer Cell. 2011 Sep 13;20(3):328-40
references: 21907924
references: Cell Metab. 2007 Oct;6(4):307-19
references: 17908559
references: Mol Cell. 2003 Jul;12(1):51-62
references: 12887892
references: J Neurosci. 2000 Oct 15;20(20):7622-30
references: 11027222
references: J Neurosci Res. 2011 Nov;89(11):1723-36
references: 21826702
references: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13211-6
references: 12235363
references: Cell. 2010 Jul 23;142(2):320-32
references: 20655472
references: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10851-6
references: 11526205
references: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9793-8
references: 18599449
references: Nat Neurosci. 2010 May;13(5):541-550
references: 20418875
references: Science. 2007 Jul 27;317(5837):516-9
references: 17588900
references: Development. 2011 Dec;138(24):5291-300
references: 22071110
references: Cell Stem Cell. 2008 Mar 6;2(3):241-51
references: 18371449
references: Nature. 2000 Feb 17;403(6771):795-800
references: 10693811
references: Nature. 2010 Aug 26;466(7310):1105-9
references: 20622856
references: PLoS Biol. 2010 Aug 17;8(8):
references: 20808958
references: Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3602-9
references: 17652729
references: Aging (Albany NY). 2010 Jul;2(7):415-31
references: 20634564
references: Nat Neurosci. 2008 Sep;11(9):1024-34
references: 19160500
references: Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13736-41
references: 20631301
references: Nat Rev Neurosci. 2008 Nov;9(11):839-55
references: 18931697
references: Nature. 1988 Jun 9;333(6173):560-2
references: 3287176
references: J Clin Invest. 2009 Oct;119(10):3048-58
references: 19729833
references: Genesis. 2007 Sep;45(9):593-605
references: 17868096
references: Cancer Lett. 2011 Jul 1;306(1):10-4
references: 21414717
references: Stem Cells. 2009 Aug;27(8):2032-43
references: 19544429
references: Mol Cell Neurosci. 2003 Oct;24(2):476-88
references: 14572468
references: Oncogene. 2009 Jun 11;28(23):2266-75
references: 19421151
references: Cell. 1988 Apr 22;53(2):309-19
references: 2834067
references: Mol Cell Neurosci. 2000 Mar;15(3):314-29
references: 10736207
references: J Neurosci. 2010 Jul 28;30(30):10220-32
references: 20668205
references: Cell Metab. 2011 Aug 3;14(2):151-3
references: 21803285
references: Neuron. 2000 Feb;25(2):317-29
references: 10719888
references: Blood. 2011 Jan 13;117(2):440-50
references: 20966168
references: Development. 2012 Sep;139(18):3422-31
references: 22874917
references: J Neurosci. 2010 Jul 21;30(29):9695-707
references: 20660252
references: J Neurosci. 2007 Mar 7;27(10):2606-16
references: 17344398
references: Cell. 2011 Jul 22;146(2):209-21
references: 21737130
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9
references: 12960381
references: Science. 2004 Dec 17;306(5704):2105-8
references: 15604409
references: Cell. 1995 Jun 2;81(5):727-36
references: 7774014
references: EMBO J. 2007 Jul 11;26(13):3169-79
references: 17581637
references: Aging Cell. 2007 Dec;6(6):759-67
references: 17877786
references: Mol Cell Biol. 2006 Jan;26(1):28-38
references: 16354677
references: Nature. 2005 Mar 3;434(7029):113-8
references: 15744310
references: J Neurosci. 2010 Aug 18;30(33):11011-27
references: 20720108
references: Nat Commun. 2010 Apr 12;1:3
references: 20975665
references: Cell Metab. 2008 Oct;8(4):333-41
references: 18840364
references: Glia. 1996 Jun;17(2):83-93
references: 8776576
references: J Neurochem. 2008 Oct;107(1):1-19
references: 18643793
references: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15599-604
references: 18829436
references: Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19162-7
references: 19855010
references: J Neurosci. 2006 Oct 25;26(43):10967-83
references: 17065439
references: J Immunol. 1973 Jan;110(1):139-43
references: 4631068
references: Cell Metab. 2008 Nov;8(5):347-58
references: 19046567
references: FEBS Lett. 2004 Aug 27;573(1-3):83-92
references: 15327980
references: Mol Cell Neurosci. 2004 Feb;25(2):252-62
references: 15019942