Activated CREB Is Sufficient to Overcome Inhibitors in Myelin and Promote Spinal Axon Regeneration In Vivo

Gao, Ying; Deng, Kung-Li; Hou, Jingli; Bryson, J. Barney; Barco, Ángel; Nikulina, Elena; Spencer, Tim; Mellado, Wilfredo; Kandel, Eric R.; Filbin, Marie T.

doi:10.1016/j.neuron.2004.10.030

Cited by 319 publications

(260 citation statements)

References 48 publications

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“…When expressed in PC12 cells and in adult rat dissociated DRG neurons, DNROCK significantly inhibits the effects of myelin protein and promotes neurite initiation and elongation. Crude CNS myelin substrates prepared from rat brain contain several inhibitors that block neurite outgrowth [26,27] . We have demonstrated that ROCK inhibition stimulates axonal outgrowth over myelin substrates.…”

Section: Discussionmentioning

confidence: 99%

Expression of a dominant-negative Rho-kinase promotes neurite outgrowth in a microenvironment mimicking injured central nervous system

2010

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Aim: To investigate whether lentiviral vector (LV)-mediated expression of a dominant negative mutant Rho-kinase (DNROCK) could inhibit activation of the Rho/ROCK signaling pathway and promote neurite outgrowth in a hostile microenvironment mimicking the injured central nervous system (CNS) in vitro. Methods: Lentiviral stock was produced using the three-plasmid system by transfecting HEK293 cells. Myelin prepared from rat brain was purified by two rounds of discontinuous density gradient centrifugation and osmotic disintegration. Differentiated PC12 cells and dissociated adult rat dorsal root ganglion (DRG) neurons were transduced with either LV/DNROCK or LV/green fluorescent protein (GFP) and seeded on solubilized myelin proteins. The effect of DNROCK on growth cone morphology was tested by rhodamine-conjugated phalloidin staining. Expression of DNROCK was determined by immunoblotting. The length of the longest neurite, the percentage of neurite-bearing neurons, or the total process outgrowth for all transduced neurons were measured by using the Scion image analysis program.

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Section: Discussionmentioning

confidence: 99%

Expression of a dominant-negative Rho-kinase promotes neurite outgrowth in a microenvironment mimicking injured central nervous system

2010

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“…MAG is a known inhibitor of regeneration in the spinal cord (Filbin 1995, Gao, et al 2004), but is also implicated in the inhibition of peripheral nerve regeneration (Schafer, et al 1996). Stimulus-induced activation of the transcription factor CREB through phosphorylation of its serine residues can overcome MAG-mediated inhibition of regeneration (Gao, et al 2004, Lonze andGinty 2002).…”

Section: Discussionmentioning

confidence: 99%

“…To test this hypothesis, we performed quantitative serial in vivo imaging in XFP mice (Feng, et al 2000), and corroborated our findings with assays for motor and sensory reinnervation. Assays for myelination, and cAMP regulatory element binding (CREB) protein expression, a transcription factor whose upregulation may be instrumental in overcoming the inhibitory influences of myelin-associated glycoprotein (MAG) on nerve regeneration were also evaluated (Gao, et al 2004). We compared a repair with epineurotomy to an atraumatic sleeve repair with and without proximal compression since previous work suggests that compression upregulates sprouting of small diameter unmyelinated axons (Mackinnon, et al 1986).…”

Section: Introductionmentioning

confidence: 99%

Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy

Hayashi

Pannucci

Moradzadeh³

et al. 2008

Experimental Neurology

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End-to-side (ETS) nerve repair remains an area of intense scrutiny for peripheral nerve surgeonscientists. In this technique, the transected end of an injured nerve, representing the "recipient" is sutured to the side of an uninjured "donor" nerve. Some work suggests that the recipient limb is repopulated with regenerating collateral axonal sprouts from the donor nerve that go on to form functional synapses. Significant, unresolved questions include whether the donor nerve needs to be injured to facilitate regeneration, and whether a single donor neuron is capable of projecting additional axons capable of differentially innervating disparate targets. We serially imaged living transgenic mice (n=66) expressing spectral variants of GFP in various neuronal subsets after undergoing previously described atraumatic, compressive, or epineurotomy forms of ETS repair (n=22 per group). To evaluate the source, and target innervation of these regenerating axons, nerve morphometry and retrograde labeling was further supplemented by confocal microscopy as well as Western blot analysis. Either compression or epineurotomy with inevitable axotomy were required to facilitate axonal regeneration into the recipient limb. Progressively more injurious models were associated with improved recipient nerve reinnervation (epineurotomy: 184±57.6 myelinated axons; compression: 78.9±13.8; atraumatic: 0), increased Schwann cell proliferation (epineurotomy: 72.2% increase; compression: 39% increase) and cAMP response-element binding protein expression at the expense of a net deficit in donor axon counts distal to the repair. These differences were manifest by 150 days, at which point quantitative evidence for pruning was obtained. We conclude that ETS repair relies upon injury to the donor nerve.

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“…Moreover, injection of cAMP into the cell body of DRG neurons resulted in the regeneration of injured spinal axons from the cAMP-injected cell bodies (Neumann et al, 2002;Qiu et al, 2002). Subsequent studies by Filbin and colleagues identified target genes and transcription factors in response to increased cAMP, such as Arg1 and CREB, which have been shown to counteract the inhibitory effect of myelin Gao et al, 2004).…”

Section: Intracellular Signalingmentioning

confidence: 99%

White matter inhibitors in CNS axon regeneration failure

Xie

Zheng

2008

Experimental Neurology

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Multiple lines of evidence have indicated that the inability of adult mammalian central nervous system (CNS) axons to regenerate after injury is partly due to the growth inhibitory property of central myelin. Three prototypical myelin-associated inhibitors of neurite outgrowth have been identified, including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp). These inhibitory ligands, their receptors and signaling pathways are being intensively investigated for their roles in CNS axon regeneration failure. In addition, several members of the axon guidance molecules have been implicated in restricting CNS axon regeneration, some of which are expressed by mature oligodendrocytes. Here we review in vitro and in vivo studies of these molecules in neurite growth and in axon regeneration failure and discuss the implications of these studies. While the increasing number of potential axon regeneration inhibitors highlights the complexity of the restrictive CNS environment, it provides new windows of opportunity as well as new challenges for therapeutic development for spinal cord injury and related neurological conditions.

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Activated CREB Is Sufficient to Overcome Inhibitors in Myelin and Promote Spinal Axon Regeneration In Vivo

Cited by 319 publications

References 48 publications

Expression of a dominant-negative Rho-kinase promotes neurite outgrowth in a microenvironment mimicking injured central nervous system

Expression of a dominant-negative Rho-kinase promotes neurite outgrowth in a microenvironment mimicking injured central nervous system

Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy

White matter inhibitors in CNS axon regeneration failure

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