Faculty Collaboration Database

KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS. J Neurosci 2017 Oct 04;37(40):9632-9644

Date

09/06/2017

Pubmed ID

28871032

Pubmed Central ID

PMC5628408

DOI

10.1523/JNEUROSCI.0643-16.2017

Scopus ID

2-s2.0-85030656568 (requires institutional sign-in at Scopus site)   78 Citations

Abstract

Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Krüppel-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 Krüppel-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.

Author List

Apara A, Galvao J, Wang Y, Blackmore M, Trillo A, Iwao K, Brown DP Jr, Fernandes KA, Huang A, Nguyen T, Ashouri M, Zhang X, Shaw PX, Kunzevitzky NJ, Moore DL, Libby RT, Goldberg JL

Author

Murray Blackmore PhD Assistant Professor in the School of Allied Health department at Marquette University

MESH terms used to index this publication - Major topics in bold

Age Factors
Animals
Axons
Base Sequence
Brain
Cells, Cultured
Central Nervous System
Female
Kruppel-Like Transcription Factors
Male
Mice
Mitogen-Activated Protein Kinase 10
Nerve Regeneration
Optic Nerve Injuries
Organ Culture Techniques
Protein Binding
Rats
Retinal Ganglion Cells