Enhancing intrinsic growth capacity promotes adult CNS regeneration

Yang, Ping; Ye, Zhong

doi:10.1016/j.jns.2011.08.037

Cited by 55 publications

(32 citation statements)

References 70 publications

(117 reference statements)

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“…The APC-Cdh1 mediates the SnoN protein to regulate cell-intrinsic axonal morphogenesis (Matz, 1995;Topsakal et al, 2003;Lasorella et al, 2006;Stegmüller et al, 2008;Yang and Yang, 2012). Results of the present study indicated that the expression of Cdh1 mRNA in the operation group was significantly higher than that of the normal group, which, along with results of previous study, suggest that Cdh1 may act to stop axonal regeneration in spinal cord injuries.…”

Section: Discussionsupporting

confidence: 77%

Effect of lentivirus-mediated RNA interference of APC-Cdh1 expression on spinal cord injury in rats

Yao

Zhang

et al. 2014

Genet. Mol. Res.

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ABSTRACT. This study investigated cadherin-1 (Cdh1) expression in the sensorimotor cortex of rats after spinal cord injury (SCI). The repairing effect of Cdh1 was evaluated by silencing its expression with lentivirus-mediated RNAi. Twenty male Sprague-Dawley (SD) rats were randomly divided into a normal group and an operation group. Rats of the operation group were given SCI by the Allen method (T10-T11). Cdh1 expression in the sensorimotor cortex was examined by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis. Thirty male SD rats were divided into a sham-operation (SO) group, a lentivirus vector (LV) group, and a recombinant lentivirus (RL) group. Rat behavior was evaluated using the Basso-BeattieBresnahan (BBB) test every week. Ten days after injection, Cdh1 expression was examined by quantitative real-time PCR and Western blot. Six weeks after injury, animals were injected with biotinylated dextran amine-Texas Red (BDA-TR), and then at 8 weeks, spinal cords were removed and sectioned in serial order. The expression of Cdh1 RNA interference of APC-Cdh1 on spinal cord injury in rats mRNA was significantly higher in the operation than in the normal group (P < 0.05). The expression of Cdh1 mRNA was lower in the RL than in the SO or LV groups at 10 days after injection (P < 0.05). In addition, the BBB score was higher for the RL than for the SO or LV groups at 6 weeks after injury (P < 0.05). A novel population of BDA-labeled axons was observed extending past the lesion in the RL group, which was rarely observed in the SO and LV groups. These results suggest that the anaphase-promoting complex-Cdh1 may play an important role in inhibiting axonal growth.

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Section: Discussionsupporting

confidence: 77%

Effect of lentivirus-mediated RNA interference of APC-Cdh1 expression on spinal cord injury in rats

Yao

Zhang

et al. 2014

Genet. Mol. Res.

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“…The promoting effect of a first lesion has been demonstrated in the case of the "conditioning lesion" of dorsal root neurons, in which regeneration of the central axon is facilitated after the peripheral axon has been severed (12,19). Unlike the conditioning effect, however, the promoting effect we document here is localized at, or distal to, the site of the first nerve cut.…”

Section: Discussionmentioning

confidence: 52%

Dynamics of axonal regeneration in adult and aging zebrafish reveal the promoting effect of a first lesion

Graciarena

Dambly‐Chaudière

Ghysen

2014

Proc. Natl. Acad. Sci. U.S.A.

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Axonal regeneration is a major issue in the maintenance of adult nervous systems, both after nerve injuries and in neurodegenerative diseases. However, studying this process in vivo is difficult or even impossible in most vertebrates. Here we show that the posterior lateral line (PLL) of zebrafish is a suitable system to study axonal regeneration in vivo because of both the superficial location and reproducible spatial arrangement of neurons and targets, and the possibility of following reinnervation in live fish on a daily basis. Axonal regeneration after nerve cut has been demonstrated in this system during the first few days of life, leading to complete regeneration within 24 h. However, the potential for PLL nerve regeneration has not been tested yet beyond the early larval stage. We explore the regeneration potential and dynamics of the PLL nerve in adult zebrafish and report that regeneration occurs throughout adulthood. We observed that irregularities in the original branching pattern are faithfully reproduced after regeneration, suggesting that regenerating axons follow the path laid down by the original nerve branches. We quantified the extent of target reinnervation after a nerve cut and found that the latency before the nerve regenerates increases with age. This latency is reduced after a second nerve cut at all ages, suggesting that a regeneration-promoting factor induced by the first cut facilitates regeneration on a second cut. We provide evidence that this factor remains present at the site of the first lesion for several days and is intrinsic to the neurons.Schwann cells | axonogenesis | neuromast | sensory system T he potential of adult neurons to regenerate their axons and to reinnervate target organs after injury is not as well understood as early axonogenesis. Whether and how this capability is modified on aging is an even less explored area. In all vertebrates studied so far, neurons of the peripheral nervous system retain the ability to reextend peripheral axons and reestablish functional connections. This ability is thought to involve intrinsic mechanisms of repair as well as extrinsic signals from the local environment, mostly coming from Schwann cells and macrophages (1).The posterior lateral line (PLL) of fish is a convenient yet unexplored sensory system to address the issue of axonal regeneration throughout adulthood. The PLL comprises a set of superficial mechanosensory organs called neuromasts, which are distributed over the body and tail. Neuromasts are composed of a core of mechanosensory hair cells providing information about the local water flow, surrounded by accessory cells. The afferent neurons innervating neuromasts are clustered in a ganglion posterior to the otic vesicle, and their peripheral axons extend toward the tail, right under the skin. This sensory system is involved in a large repertoire of behaviors (2).The juvenile PLL of zebrafish comprises four lines of neuromasts that extend at different dorsoventral levels, totaling about 50 organs (3). This pattern is estab...

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“…The transcription factors C/EBP␤ and vertebrate homologs to Drosophila Krüppel increase in expression early during the regenerative response of mouse facial nerve and zebrafish optic nerve, respectively, to promote regeneration and regulate GAP-43 (Nadeau et al, 2005;Kajimura et al, 2007;Veldman et al, 2007). Accumulating evidence points to post-transcriptional regulatory mechanisms as additional key determinants of axon regeneration (Park et al, 2008;Yan et al, 2009;Yang and Yang, 2012). GAP-43 and NF-M are both under strong post-transcriptional control during optic axon regeneration and, in both cases, this control further modulates the primary transcripts to effect downstream changes in cytosolic mRNA levels and translation (PerroneBizzozero et al, 1991;Ananthakrishnan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein K, an RNA-Binding Protein, Is Required for Optic Axon Regeneration inXenopus laevis

Liu

Yu²,

Deaton³

et al. 2012

J. Neurosci.

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Axotomized optic axons of Xenopus laevis, in contrast to those of mammals, retain their ability to regenerate throughout life. To better understand the molecular basis for this successful regeneration, we focused on the role of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein (hnRNP) K, because it is required for axonogenesis during development and because several of its RNA targets are under strong post-transcriptional control during regeneration. At 11 d after optic nerve crush, hnRNP K underwent significant translocation into the nucleus of retinal ganglion cells (RGCs), indicating that the protein became activated during regeneration. To suppress its expression, we intravitreously injected an antisense Vivo-Morpholino oligonucleotide targeting hnRNP K. In uninjured eyes, it efficiently knocked down hnRNP K expression in only the RGCs, without inducing either an axotomy response or axon degeneration. After optic nerve crush, staining for multiple markers of regenerating axons showed no regrowth of axons beyond the lesion site with hnRNP K knockdown. RGCs nonetheless responded to the injury by increasing expression of multiple growthassociated RNAs and experienced no additional neurodegeneration above that normally seen with optic nerve injury. At the molecular level, hnRNP K knockdown during regeneration inhibited protein, but not mRNA, expression of several known hnRNP K RNA targets (NF-M, GAP-43) by compromising their efficient nuclear transport and disrupting their loading onto polysomes for translation. Our study therefore provides evidence of a novel post-transcriptional regulatory pathway orchestrated by hnRNP K that is essential for successful CNS axon regeneration.

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Enhancing intrinsic growth capacity promotes adult CNS regeneration

Cited by 55 publications

References 70 publications

Effect of lentivirus-mediated RNA interference of APC-Cdh1 expression on spinal cord injury in rats

Effect of lentivirus-mediated RNA interference of APC-Cdh1 expression on spinal cord injury in rats

Dynamics of axonal regeneration in adult and aging zebrafish reveal the promoting effect of a first lesion

Heterogeneous Nuclear Ribonucleoprotein K, an RNA-Binding Protein, Is Required for Optic Axon Regeneration inXenopus laevis

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