PMID- 28871032
OWN - NLM
STAT- MEDLINE
DCOM- 20171012
LR  - 20190114
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 37
IP  - 40
DP  - 2017 Oct 4
TI  - KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS.
PG  - 9632-9644
LID - 10.1523/JNEUROSCI.0643-16.2017 [doi]
AB  - Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity 
      during development in concert with changes in Kruppel-like transcription factors 
      (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells 
      (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is 
      normally upregulated 250-fold in RGC development, promotes long-distance optic 
      nerve regeneration in adult rats of both sexes. We identified a novel binding 
      partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is 
      critical for KLF9's axon-growth-suppressive activity. Interfering with a 
      JNK3-binding domain or mutating two newly discovered serine phosphorylation 
      acceptor sites, Ser106 and Ser110, effectively abolished KLF9's neurite growth 
      suppression in vitro and promoted axon regeneration in vivo These findings 
      demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in 
      regenerative failure in the optic nerve and suggest new therapeutic strategies to 
      promote axon regeneration in the adult CNS.SIGNIFICANCE STATEMENT Injured CNS 
      nerves fail to regenerate spontaneously. Promoting intrinsic axon growth capacity 
      has been a major challenge in the field. Here, we demonstrate that knocking down 
      Kruppel-like transcription factor 9 (KLF9) via shRNA promotes long-distance axon 
      regeneration after optic nerve injury and uncover a novel and important KLF9-JNK3 
      interaction that contributes to axon growth suppression in vitro and regenerative 
      failure in vivo These studies suggest potential therapeutic approaches to promote 
      axon regeneration in injury and other degenerative diseases in the adult CNS.
CI  - Copyright (c) 2017 the authors 0270-6474/17/379632-13$15.00/0.
FAU - Apara, Akintomide
AU  - Apara A
AUID- ORCID: 0000-0003-0008-8332
AD  - Bascom Palmer Eye Institute.
AD  - Interdisciplinary Stem Cell Institute, and.
AD  - Neuroscience Graduate Program, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
FAU - Galvao, Joana
AU  - Galvao J
AUID- ORCID: 0000-0002-7699-9901
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093, jgalvao@stanford.edu.
AD  - Byers Eye Institute, Stanford University School of Medicine, Palo Alto, 
      California 94303.
FAU - Wang, Yan
AU  - Wang Y
AD  - Interdisciplinary Stem Cell Institute, and.
AD  - Neuroscience Graduate Program, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
FAU - Blackmore, Murray
AU  - Blackmore M
AD  - Department of Biomedical Sciences at Marquette University, Milwaukee, Wisconsin 
      53201.
FAU - Trillo, Allison
AU  - Trillo A
AUID- ORCID: 0000-0002-5251-0155
AD  - Bascom Palmer Eye Institute.
AD  - Interdisciplinary Stem Cell Institute, and.
FAU - Iwao, Keiichiro
AU  - Iwao K
AUID- ORCID: 0000-0002-4102-9374
AD  - Bascom Palmer Eye Institute.
AD  - Interdisciplinary Stem Cell Institute, and.
FAU - Brown, Dale P Jr
AU  - Brown DP Jr
AD  - Bascom Palmer Eye Institute.
AD  - Interdisciplinary Stem Cell Institute, and.
FAU - Fernandes, Kimberly A
AU  - Fernandes KA
AD  - Flaum Eye Institute, University of Rochester Medical Center, Rochester, New York 
      14642, and.
FAU - Huang, Abigail
AU  - Huang A
AUID- ORCID: 0000-0002-2885-3131
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
FAU - Nguyen, Tu
AU  - Nguyen T
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
FAU - Ashouri, Masoumeh
AU  - Ashouri M
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
FAU - Zhang, Xiong
AU  - Zhang X
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
FAU - Shaw, Peter X
AU  - Shaw PX
AUID- ORCID: 0000-0001-7392-6224
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
FAU - Kunzevitzky, Noelia J
AU  - Kunzevitzky NJ
AUID- ORCID: 0000-0002-8993-6520
AD  - Bascom Palmer Eye Institute.
AD  - Interdisciplinary Stem Cell Institute, and.
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
AD  - Center for Computational Science, University of Miami, Miami, Florida 33146.
FAU - Moore, Darcie L
AU  - Moore DL
AUID- ORCID: 0000-0002-0854-7655
AD  - Bascom Palmer Eye Institute.
AD  - Neuroscience Graduate Program, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
AD  - Department of Neuroscience, University of Wisconsin, Madison, Wisconsin 53705.
FAU - Libby, Richard T
AU  - Libby RT
AUID- ORCID: 0000-0003-2844-7632
AD  - Flaum Eye Institute, University of Rochester Medical Center, Rochester, New York 
      14642, and.
FAU - Goldberg, Jeffrey L
AU  - Goldberg JL
AUID- ORCID: 0000-0002-1390-7360
AD  - Bascom Palmer Eye Institute.
AD  - Interdisciplinary Stem Cell Institute, and.
AD  - Neuroscience Graduate Program, University of Miami Miller School of Medicine, 
      Miami, Florida 33136.
AD  - Shiley Eye Center, University of California San Diego, La Jolla, California 
      92093.
AD  - Byers Eye Institute, Stanford University School of Medicine, Palo Alto, 
      California 94303.
LA  - eng
GR  - P30 EY014801/EY/NEI NIH HHS/United States
GR  - P30 EY022589/EY/NEI NIH HHS/United States
GR  - R01 EY022129/EY/NEI NIH HHS/United States
GR  - R01 EY018606/EY/NEI NIH HHS/United States
GR  - R01 EY025693/EY/NEI NIH HHS/United States
GR  - U01 NS074490/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20170904
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 148686-29-7 (Klf9 protein, rat)
RN  - EC 2.7.1.- (Mitogen-Activated Protein Kinase 10)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Axons/*physiology
MH  - Base Sequence
MH  - Brain/*physiology
MH  - Cells, Cultured
MH  - Central Nervous System/physiology
MH  - Female
MH  - Kruppel-Like Transcription Factors/deficiency/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 10/genetics/*metabolism
MH  - Nerve Regeneration/*physiology
MH  - Optic Nerve Injuries/genetics/metabolism
MH  - Organ Culture Techniques
MH  - Protein Binding/physiology
MH  - Rats
MH  - Retinal Ganglion Cells/physiology
PMC - PMC5628408
OTO - NOTNLM
OT  - Jnk
OT  - KLFs
OT  - regeneration
OT  - survival
EDAT- 2017/09/06 06:00
MHDA- 2017/10/13 06:00
PMCR- 2018/04/04
CRDT- 2017/09/06 06:00
PHST- 2016/02/26 00:00 [received]
PHST- 2017/08/22 00:00 [revised]
PHST- 2017/08/23 00:00 [accepted]
PHST- 2017/09/06 06:00 [pubmed]
PHST- 2017/10/13 06:00 [medline]
PHST- 2017/09/06 06:00 [entrez]
PHST- 2018/04/04 00:00 [pmc-release]
AID - JNEUROSCI.0643-16.2017 [pii]
AID - 0643-16 [pii]
AID - 10.1523/JNEUROSCI.0643-16.2017 [doi]
PST - ppublish
SO  - J Neurosci. 2017 Oct 4;37(40):9632-9644. doi: 10.1523/JNEUROSCI.0643-16.2017. 
      Epub 2017 Sep 4.