Abstract

Neurons in the adult mammalian central nervous system (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 find that knockdown of KLF9, an axon growth suppressor normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rat of both sexes. We identify a novel binding partner, MAPK10/JNK3 kinase, and find JNK3 is critical for KLF9's axon growth suppressive activity. Interfering with a JNK3-binding domain (JBD), or mutating two newly discovered serine phosphorylation acceptor sites, Ser106/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 STATEMENTInjured central nervous system (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 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.

View details for PubMedID 28871032