The role of mitochondrial fission/fusion in CNS axon regeneration Central nervous system (CNS) disease or injury is often accompanied by progressive axon degeneration, leading to lost sensory, motor, or cognitive abilities, with little o no regenerative response. In search of signaling factors to restore degenerated CNS axons, we identified a group of developmentally regulated transcription factors, the Kruppel-like transcription factors (KLFs), which differentially suppress or enhance hippocampal, corticospinal neuron, and retinal ganglion cell (RGC) axon growth. However, the downstream mechanisms by which KLFs regulate axon growth are unknown. Evidence suggests one downstream effector may be mitochondrial (Mt) fission/fusion dynamics. We recently showed that suppressing fission (increasing fusion) leads to a loss in axon growth inhibition by chondroitin sulfate proteoglycans, supporting a hypothesis in which CNS axon growth and guidance is regulated by Mt fission-fusion dynamics. These data also suggest suppressing Mt fission is a potential therapeutic strategy for improving axon regeneration after CNS trauma or disease. To identify whether Mt fission/fusion mechanisms also underlie the axon suppressing/enhancing activity of KLFs, we are investigating the potential ability for KLFs to critically regulate Mt genes for axon growth. Pertinent to our previous findings, we found that axon growth-suppressing KLF9 increased and growth- promoting KLF7 decreased the genetic expression of mitochondrial fission process 1,18 kDa (MTP18), a positive regulator of Mt fission, supporting the hypothesis that increased fission is inhibitory for axon growth in CNS neurons. Furthermore, our recent data analyzing exome sequencing of familial axonopathies also pointed to a disease association with a number of mitochondrial proteins thought to act on fission/fusion dynamics, including MTP18. Therefore, we hypothesize that KLF7/9-mediated regulation of the mitochondrial fission enhancer MTP18 regulates intrinsic axon growth ability in CNS neurons. To address this hypothesis, we will express/knockdown MTP18 in combination with or independent of KLF7/9 expression/knockdown in RGCs both in vitro and in vivo, identifying the neuronal role of MTP18 in regulating Mt fission/fusion dynamics, CNS axon growth and guidance, and KLF7/9-mediated axon regeneration. The overall goal is to improve our understanding of how Mt fission/fusion regulates axon regeneration and identify strategies for restoring axon growth after CNS injury or disease.
The clinical manifestation of central nervous system (CNS) injury or disease often presents after permanent degeneration of neuronal connections with their targets, with few clinically available treatment options. The goals of this project are to investigte the underlying molecular mechanisms by which mitochondrial dynamics regulate axon growth and regeneration. Ultimately these studies may generate novel treatment strategies for patients experiencing CNS degenerative diseases and/or injuries.
| Takihara, Yuji; Inatani, Masaru; Eto, Kei et al. (2015) In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS. Proc Natl Acad Sci U S A 112:10515-20 |
