1. Optic nerve regeneration screen identifies multiple genes restricting adult neural repair.
- Author
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Lindborg JA, Tran NM, Chenette DM, DeLuca K, Foli Y, Kannan R, Sekine Y, Wang X, Wollan M, Kim IJ, Sanes JR, and Strittmatter SM
- Subjects
- Animals, Axons metabolism, Axons pathology, CRISPR-Cas Systems, Dependovirus genetics, Female, Gene Editing, Gene Expression Regulation, Genetic Association Studies, HEK293 Cells, Humans, Interleukins genetics, Interleukins metabolism, MAP Kinase Kinase Kinases genetics, MAP Kinase Kinase Kinases metabolism, Male, Mice, Inbred C57BL, Mice, Transgenic, Optic Nerve pathology, Optic Nerve physiopathology, Optic Nerve Injuries metabolism, Optic Nerve Injuries pathology, Optic Nerve Injuries physiopathology, Retinal Ganglion Cells metabolism, Retinal Ganglion Cells pathology, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Interleukin-22, Mice, Nerve Regeneration genetics, Neurogenesis genetics, Optic Nerve metabolism, Optic Nerve Injuries genetics
- Abstract
Adult mammalian central nervous system (CNS) trauma interrupts neural networks and, because axonal regeneration is minimal, neurological deficits persist. Repair via axonal growth is limited by extracellular inhibitors and cell-autonomous factors. Based on results from a screen in vitro, we evaluate nearly 400 genes through a large-scale in vivo regeneration screen. Suppression of 40 genes using viral-driven short hairpin RNAs (shRNAs) promotes retinal ganglion cell (RGC) axon regeneration after optic nerve crush (ONC), and most are validated by separate CRISPR-Cas9 editing experiments. Expression of these axon-regeneration-suppressing genes is not significantly altered by axotomy. Among regeneration-limiting genes, loss of the interleukin 22 (IL-22) cytokine allows an early, yet transient, inflammatory response in the retina after injury. Reduced IL-22 drives concurrent activation of signal transducer and activator of transcription 3 (Stat3) and dual leucine zipper kinase (DLK) pathways and upregulation of multiple neuron-intrinsic regeneration-associated genes (RAGs). Including IL-22, our screen identifies dozens of genes that limit CNS regeneration. Suppression of these genes in the context of axonal damage could support improved neural repair., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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