Editors' ChoiceTissue Regeneration

Regenerating CNS neurons

Science Signaling  26 May 2015:
Vol. 8, Issue 378, pp. ec137
DOI: 10.1126/scisignal.aac6241

Whereas peripheral neurons can regenerate after injury, for the most part neurons in the central nervous system (CNS) cannot. Comparison of the transcriptome in neurons that can regenerate with those that cannot has provided some clues to the molecular pathways involved. Now, Belin et al. examined such changes at the protein level in CNS neurons using mouse retinal ganglion cells (RGCs), specialized neurons of the optic nerve that transmit visual information from the retina to the brain. In mice with RGCs that express yellow fluorescent protein (YFP-17 mice), the optic nerve of one eye was crushed in a manner that transected all RGC axons, then RGCs were isolated from the injured eye and uninjured eye. Mass spectrometry identified a subset of proteins that were either increased or decreased in the injured RGCs. Pathway analysis then indicated many proteins previously implicated in regenerative mechanisms as well as several new ones, including the Huntington’s disease–associated protein Huntingtin (Htt), the inflammation-associated transcription factor NF-κB, and the proliferation-regulating transcription factor c-Myc. The authors focused on c-Myc and determined that the reduction in c-Myc was associated with reduced transcript abundance in injured RGCs. Overexpressing c-Myc before injury by injecting a c-Myc–encoding adenovirus vector into the vitreous body of the eye doubled the survival of injured RGCs and increased the growth of axons therein. Likewise, transient activation of c-Myc before injury in mice expressing tamoxifen-inducible c-Myc improved RGC survival and axon growth. In a more clinically relevant model, delayed overexpression of c-Myc in the tamoxifen-inducible mice a day after optic nerve injury had the same effects. In another mouse model in which the phosphatase PTEN is knocked down to promote neuronal regeneration, overexpressing c-Myc further enhanced—whereas knocking out c-Myc impaired—axon regeneration, indicating that c-Myc is critical to the regenerative mechanism. The findings suggest that supplementing c-Myc to CNS neurons after injury may be therapeutic strategy to stimulate regeneration.

S. Belin, H. Nawabi, C. Wang, S. Tang, A. Latremoliere, P. Warren, H. Schorle, C. Uncu, C. J. Woolf, Z. He, J. A. Steen, Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 86, 1000–1014 (2015). [PubMed]