Abstract
Cytokine-induced activation of signal transducer and activator of transcription 3 (STAT3) promotes the regrowth of damaged axons in the adult central nervous system (CNS). Here we show that KLF4 physically interacts with STAT3 upon cytokine-induced phosphorylation of tyrosine 705 (Y705) on STAT3. This interaction suppresses STAT3-dependent gene expression by blocking its DNA-binding activity. The deletion of KLF4 in vivo induces axon regeneration of adult retinal ganglion cells (RGCs) via Janus kinase (JAK)-STAT3 signalling. This regeneration can be greatly enhanced by exogenous cytokine treatment, or removal of an endogenous JAK-STAT3 pathway inhibitor called suppressor of cytokine signalling 3 (SOCS3). These findings reveal an unexpected cross-talk between KLF4 and activated STAT3 in the regulation of axon regeneration that might have therapeutic implications in promoting repair of injured adult CNS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axons / metabolism*
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Axons / pathology
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COS Cells
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Chlorocebus aethiops
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Female
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Gene Expression Regulation
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Genes, Reporter
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / deficiency
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Kruppel-Like Transcription Factors / genetics*
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Luciferases / genetics
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Luciferases / metabolism
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Male
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Mice
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Mice, Transgenic
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Nerve Regeneration / genetics*
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Optic Nerve Injuries
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Phosphorylation
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Protein Binding
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Retinal Ganglion Cells / metabolism*
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Retinal Ganglion Cells / pathology
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / genetics*
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Suppressor of Cytokine Signaling Proteins / metabolism
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Tyrosine / metabolism
Substances
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Tyrosine
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Luciferases