Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury

SummaryPeripheral nerve regeneration after injury requires a broad program of transcriptional changes. We investigated the basis for the enhanced nerve regenerative capacity of the CAST/Ei mouse strain relative to C57BL/6 mice. RNA sequencing of dorsal root ganglia (DRG) showed a CAST/Ei specific upregulation of Ascl1 after injury. Ascl1 overexpression in C57BL/6 mice DRG neurons enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is down-regulated in CAST/Ei mice. Inhibition of miR-7048-3p enhances neurite outgrowth. Following injury, CAST/Ei neurons largely retained their mature neuronal profile as determined by single cell RNAseq, whereas the C57BL/6 neurons acquired an immature profile. These findings suggest that one facet of the enhanced regenerative phenotype is preservation of neuronal identity in response to injury.

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Enhanced Neuronal Regeneration in the CAST/Ei Mouse Strain Is Linked to Expression of Differentiation Markers after Injury

Cell Reports ◽

10.1016/j.celrep.2017.07.010 ◽

2017 ◽

Vol 20 (5) ◽

pp. 1136-1147 ◽

Cited By ~ 17

Author(s):

Véronique Lisi ◽

Bhagat Singh ◽

Michel Giroux ◽

Elmer Guzman ◽

Michio W. Painter ◽

...

Keyword(s):

Mouse Strain ◽

Neuronal Regeneration ◽

Differentiation Markers

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The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011917 ◽

2020 ◽

Vol 295 (25) ◽

pp. 8374-8386 ◽

Cited By ~ 1

Author(s):

Dong Wang ◽

Yanping Chen ◽

Mingwen Liu ◽

Qianqian Cao ◽

Qihui Wang ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Neurite Outgrowth ◽

Nerve Injury ◽

Functional Recovery ◽

Peripheral Nerve Injury ◽

Axon Regeneration ◽

Neuronal Regeneration ◽

Competing Endogenous Rna ◽

Drg Neurons

The intrinsic regeneration ability of neurons is a pivotal factor in the repair of peripheral nerve injury. Therefore, identifying the key modulators of nerve regeneration may help improve axon regeneration and functional recovery after injury. Unlike for classical transcription factors and regeneration-associated genes, the function of long noncoding RNAs (lncRNAs) in the regulation of neuronal regeneration remains mostly unknown. In this study, we used RNA-Seq–based transcriptome profiling to analyze the expression patterns of lncRNAs and mRNAs in rat dorsal root ganglion (DRG) following sciatic nerve injury. Analyses using the lncRNA-mRNA co-expression network, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway databases indicated that the lncRNA Arrl1 decreases neurite outgrowth after neuronal injury. shRNA-mediated Arrl1 silencing increased axon regeneration both in vitro and in vivo and improved functional recovery of the sciatic nerve. Moreover, inhibiting an identified target gene of Arrl1, cyclin-dependent kinase inhibitor 2B (Cdkn2b), markedly promoted neurite outgrowth of DRG neurons. We also found that Arrl1 acts as a competing endogenous RNA that sponges a Cdkn2b repressor, microRNA-761 (miR-761), and thereby up-regulates Cdkn2b expression during neuron regeneration. We conclude that the lncRNA Arrl1 affects the intrinsic regeneration of DRG neurons by derepressing Cdkn2b expression. Our findings indicate a role for an lncRNA-microRNA-kinase pathway in the regulation of axon regeneration and functional recovery following peripheral nerve injury in rats.

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Faculty Opinions recommendation of ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089584.544843 ◽

2007 ◽

Author(s):

Ahmet Hoke

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Drg Neurons ◽

Growth State

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The effects of gradients of nerve growth factor immobilized PCLA scaffolds on neurite outgrowth in vitro and peripheral nerve regeneration in rats

Biomaterials ◽

10.1016/j.biomaterials.2013.05.080 ◽

2013 ◽

Vol 34 (29) ◽

pp. 7086-7096 ◽

Cited By ~ 96

Author(s):

Shuo Tang ◽

Jixiang Zhu ◽

Yangbin Xu ◽

Andy Peng Xiang ◽

Mei Hua Jiang ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Peripheral Nerve ◽

Neurite Outgrowth ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Nerve Growth

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Vasoinhibin Suppresses the Neurotrophic Effects of VEGF and NGF in Newborn Rat Primary Sensory Neurons

Neuroendocrinology ◽

10.1159/000477768 ◽

2017 ◽

Vol 106 (3) ◽

pp. 221-233 ◽

Cited By ~ 11

Author(s):

Ximena Castillo ◽

Zesergio Melo ◽

Alfredo Varela-Echavarría ◽

Elisa Tamariz ◽

Rodrigo M. Aroña ◽

...

Keyword(s):

Growth Factor ◽

Neurite Outgrowth ◽

Sensory Neurons ◽

Target Cells ◽

Vascular Endothelial ◽

Primary Sensory Neurons ◽

Drg Neurons ◽

Newborn Rat ◽

Akt Phosphorylation ◽

Endothelial Growth Factor

Background/Aims: Studies on the biological actions of vasoinhibins have focused mainly on endothelial cells. However, there is incipient knowledge about how vasoinhibins affect the nervous system, even if the target cells and mechanisms of action involved in these effects are unknown. Methods: In order to determine if neurons are direct targets of vasoinhibins, we examined cellular outcomes and the intracellular pathways involved in the neuronal actions of vasoinhibins using newborn rat dorsal root ganglion (DRG) neurons as a model system. Results: Vascular endothelial growth factor (VEGF) or nerve growth factor (NGF) treatment for 48 h resulted in neurite outgrowth stimulation in both DRG cultured explants and isolated primary sensory neurons. Interestingly, a recombinant vasoinhibin containing the first 123 amino acids of human prolactin antagonized the VEGF- and NGF-induced stimulation of neurite outgrowth. Vasoinhibin significantly reduced the density of neurites in DRG explants and obliterated neuritogenesis in isolated DRG neurons in primary culture, supporting a direct neuronal effect of vasoinhibin. In cultures of isolated DRG cells, virtually all β3-tubulin-labeled cells express TrkA, and the majority of these cells also express VEGFR2. Short-term VEGF or NGF treatment of DRG explants resulted in increased ERK1/2 and AKT phosphorylation, whereas incubation of DRG with the combination of either VEGF or NGF together with vasoinhibin resulted in blunted VEGF- or NGF-induced phosphorylation of both ERK1/2 and AKT. Conclusion: Our results show that primary sensory neurons are direct targets of vasoinhibin, and suggest that vasoinhibin inhibition of neurite outgrowth involves the disruption of ERK and AKT phosphorylation cascades.

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