title: B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS.
abstract: Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.
authors.affiliation: Burke Medical Research Institute, Weill Cornell Medical College of Cornell University, White Plains, NY 10605.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: O'Donovan
authors.forename: Kaijie
authors.initials: K
authors.lastname: Ma
authors.forename: Hengchang
authors.initials: H
authors.lastname: Guo
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.forename: Seung Baek
authors.initials: SB
authors.lastname: Han
authors.forename: Hyukmin
authors.initials: H
authors.lastname: Kim
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Wong
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zou
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Son
authors.forename: Zhigang
authors.initials: Z
authors.lastname: He
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology / Q000502:physiology*; D015153:Blotting, Western; D002490:Central Nervous System / Q000196:embryology* / Q000293:injuries*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
references.citation: J Neurosci. 2011 Mar 23;31(12):4569-82
references.pmid: 21430157
references.citation: Exp Neurol. 2002 Dec;178(2):259-67
references.pmid: 12504884
references.citation: Proc Natl Acad Sci U S A. 2011 May 10;108(19):E99-107
references.pmid: 21518886
references.citation: Science. 2011 Feb 18;331(6019):928-31
references.pmid: 21273450
references.citation: Nat Genet. 1999 Sep;23(1):99-103
references.pmid: 10471508
references.citation: Eur J Neurosci. 2007 Aug;26(4):828-42
references.pmid: 17714182
references.citation: Cancer Res. 2005 Dec 15;65(24):11493-500
references.pmid: 16357158
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7215-20
references.pmid: 19359495
references.citation: Curr Neurovasc Res. 2007 May;4(2):143-51
references.pmid: 17504212
references.citation: Dev Biol. 2001 Jan 15;229(2):263-70
references.pmid: 11203694
references.citation: J Neurosci Res. 2006 May 1;83(6):985-95
references.pmid: 16493686
references.citation: Cell. 2009 Sep 4;138(5):1005-18
references.pmid: 19737525
references.citation: J Proteomics. 2011 Feb 1;74(2):186-98
references.pmid: 21055488
references.citation: Exp Neurol. 2010 May;223(1):45-50
references.pmid: 20079353
references.citation: J Neurosci. 2006 Nov 15;26(46):11974-86
references.pmid: 17108171
references.citation: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7517-22
references.pmid: 22529377
references.citation: Arch Ophthalmol. 2010 Aug;128(8):1059-64
references.pmid: 20697009
references.citation: Cell. 2004 Jul 23;118(2):243-55
references.pmid: 15260993
references.citation: J Cell Biol. 2008 Mar 10;180(5):947-55
references.pmid: 18332218
references.citation: Nature. 2000 Jan 20;403(6767):312-6
references.pmid: 10659850
references.citation: J Neurosci. 2007 Jul 25;27(30):7911-20
references.pmid: 17652582
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11585-90
references.pmid: 20534446
references.citation: J Neurosci. 2013 Mar 20;33(12):5399-410
references.pmid: 23516305
references.citation: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1565-74
references.pmid: 16939975
references.citation: Development. 2011 Nov;138(22):4887-98
references.pmid: 22028026
references.citation: Exp Neurobiol. 2012 Sep;21(3):83-93
references.pmid: 23055786
references.citation: J Neurochem. 2005 Apr;93(1):72-83
references.pmid: 15773907
references.citation: Pharmacol Ther. 2013 May;138(2):155-75
references.pmid: 23348013
references.citation: Nat Neurosci. 2004 Aug;7(8):812-8
references.pmid: 15247919
references.citation: Neuron. 2012 Jun 21;74(6):1015-22
references.pmid: 22726832
references.citation: Nat Neurosci. 2009 Nov;12(11):1407-14
references.pmid: 19855390
references.citation: Nat Neurosci. 2007 May;10(5):598-607
references.pmid: 17396120
references.citation: J Neurosci. 2001 Jan 15;21(2):541-9
references.pmid: 11160433
references.citation: Science. 1995 Oct 6;270(5233):96-9
references.pmid: 7569956
references.citation: Nature. 2011 Nov 06;480(7377):372-5
references.pmid: 22056987
references.citation: Neuron. 2002 Feb 28;33(5):689-702
references.pmid: 11879647
references.citation: Nat Neurosci. 2008 Apr;11(4):488-96
references.pmid: 18344995
references.citation: Nat Neurosci. 2010 Sep;13(9):1075-81
references.pmid: 20694004
references.citation: Neuron. 2000 Feb;25(2):345-57
references.pmid: 10719890
references.citation: Neuroscience. 2007 Dec 12;150(3):665-74
references.pmid: 17964731
references.citation: Cell Death Dis. 2013 Apr 25;4:e609
references.pmid: 23618907
references.citation: Exp Eye Res. 2000 Aug;71(2):209-13
references.pmid: 10930325
references.citation: J Neurochem. 2006 Oct;99(1):13-9
references.pmid: 16899067
references.citation: Neuron. 2006 Dec 7;52(5):775-88
references.pmid: 17145500
references.citation: EMBO Rep. 2013 Oct;14(10):931-7
references.pmid: 23928811
references.citation: Science. 2008 Nov 7;322(5903):963-6
references.pmid: 18988856
references.citation: PLoS One. 2012;7(6):e38101
references.pmid: 22701605
references.citation: PLoS One. 2011 Feb 28;6(2):e17321
references.pmid: 21387003
references.citation: Mol Cell Neurosci. 2009 Jun;41(2):233-46
references.pmid: 19332123
references.citation: J Neurosci. 2009 Jun 3;29(22):7116-23
references.pmid: 19494134
references.citation: J Neurosci. 1997 Apr 15;17(8):2775-84
references.pmid: 9092599
references.citation: J Biol Chem. 2013 Nov 15;288(46):33156-70
references.pmid: 24089523
references.citation: Glia. 2009 Aug 15;57(11):1178-91
references.pmid: 19170182
references.citation: Brain Res Mol Brain Res. 2004 Mar 30;122(2):116-25
references.pmid: 15010204
references.citation: J Neurosci. 1997 Jan 15;17(2):646-58
references.pmid: 8987787
references.citation: J Neurosci. 1999 Jun 1;19(11):4305-13
references.pmid: 10341234
references.citation: Brain. 2008 Oct;131(Pt 10):2606-19
references.pmid: 18757464
references.citation: J Neurosci. 1999 Feb 1;19(3):1038-48
references.pmid: 9920667
references.citation: Neurol Res. 2009 Dec;31(10):1068-74
references.pmid: 19426585
references.citation: Neuron. 2009 Dec 10;64(5):617-23
references.pmid: 20005819
references.citation: Cell Death Dis. 2013 Jul 18;4:e734
references.pmid: 23868067
references.citation: Neuron. 2002 Jul 3;35(1):65-76
references.pmid: 12123609
references.citation: Trends Neurosci. 2012 Mar;35(3):156-63
references.pmid: 22137336