A Gene Network Perspective on Axonal Regeneration

Kesteren, Ronald E. van; Mason, Matthew R. J.; MacGillavry, Harold D.; Smit, August B.; Verhaagen, Joost

doi:10.3389/fnmol.2011.00046

Cited by 59 publications

(42 citation statements)

References 73 publications

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“…Although we and others have shown that forced expression of single pro-regenerative TFs can act to enhance axon regeneration in injured CNS neurons (6-8), it is increasingly clear that combinatorial TF treatments are more effective than single TF treatments (8, 53, 54). Indeed, in silico analyses of peripheral neurons indicates that multi-nodal transcriptional networks, rather than isolated activities by individual TFs, drives regenerative axon growth (9, 11, 39, 55-57). AP-1 factors JUN and ATF3 are classic regeneration-associated TFs, likely involved in coordinating the peripheral nerve regeneration program based on their expression patterns in transcriptional profiling datasets (58).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo

et al. 2016

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Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro-regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve axon growth in other cell types, including combinatorial overexpression of AP1 factors, overexpression of histone acetyltransferases, and pharmacological inhibitors of histone deacetylases. This insensitivity could be due to intermediate chromatin closure at the time of culture, and highlights important differences in cell culture models used to test potential pro-regenerative interventions.

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Section: Discussionmentioning

confidence: 99%

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo

et al. 2016

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“…Datasets and network tools that include physical interactions, although built largely from non-neural cell types [14, 24, 31, 44, 60], are readily available and are already being used to help prioritize TFs of interest in the context of regeneration research [13, 77, 79]. A driving assumption of this approach is that TFs with large numbers of known interactions act as hub proteins and are thus high priority targets for functional intervention.…”

Section: Physical Interactionmentioning

confidence: 99%

“…Table 1, and [41]). These transcriptional relationships are described in searchable databases including IPA and TRRUST [31, 79] and raise the possibility that similar relationships may exist in neurons. In summary, genome-wide discovery efforts focused on neurons and targeted verification of predicted transcriptional relationships offer a rapid way to expand knowledge of TF networks in regenerative neuroscience.…”

Section: Transcriptional Cross-regulationmentioning

confidence: 99%

“…Indeed, recent work in the optic system makes it plain that combinatorial gene manipulations are most effective in producing axon regeneration [6, 49, 73]. Although plausible in principle, this combinatorial perspective brings with it the challenge of identifying optimal sets of TFs [77, 79]. With well over one thousand TFs in the genome and at least a dozen already linked to regenerative axon growth in vivo (Table 1), the number of possible combinations is daunting.…”

Section: Introductionmentioning

confidence: 99%

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Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter

Venkatesh

Blackmore

2017

Neuroscience Letters

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Recovery from injuries to the central nervous system, including spinal cord injury, is constrained in part by the intrinsically low ability of many CNS neurons to mount an effective regenerative growth response. To improve outcomes, it is essential to understand and ultimately reverse these neuron-intrinsic constraints. Genetic manipulation of key transcription factors (TFs), which act to orchestrate production of multiple regeneration-associated genes, has emerged as a promising strategy. It is likely that no single TF will be sufficient to fully restore neuron-intrinsic growth potential, and that multiple, functionally interacting factors will be needed. An extensive literature, mostly from non-neural cell types, has identified potential mechanisms by which TFs can functionally synergize. Here we examine four potential mechanisms of TF/TF interaction; physical interaction, transcriptional cross-regulation, signaling-based cross regulation, and co-occupancy of regulatory DNA. For each mechanism, we consider how existing knowledge can be used to guide the discovery and effective use of TF combinations in the context of regenerative neuroscience. This mechanistic insight into TF interactions is needed to accelerate the design of effective TF-based interventions to relieve neuron-intrinsic constraints to regeneration and to foster recovery from CNS injury.

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“…Likewise, new research approaches are continually being sought to impact the progression of neurodegeneration, and to intervene in brain injury to rescue or regenerate damaged brain neurons. Further research using models such as the facial nerve reinjury model, could identify the molecular signals involved in this powerful and unique form of neuroplasticity, and lead to new ways to induce or augment neuroregeneration in patients with neurotrauma and other forms of CNS insult and disease [65,66]. Neuroimmunological approaches could provide needed new insights into the interactions between complex systems, insights that may be essential to move through barriers to devise more effective treatments for clinical neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Neuronal Atrophy: Role of Cellular Immunity in Neuroplasticity and Aging

Petitto¹

2014

J Neurol Disord

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Emerging evidence indicates that neuroimmunological changes in the brain can modify intrinsic brain processes that are involved in regulating neuroplasticity. Increasing evidence suggests that in some forms of motor neuron injury, many neurons do not die, but reside in an atrophic state for an extended period of time. In mice, facial motor neurons in the brain undergo a protracted period of degeneration or atrophy following resection of their peripheral axons. Reinjuring the proximal nerve stump of the chronically resected facial nerve stimulates a robust reversal of motor neuron atrophy which results in marked increases in both the number and size of injured motor neurons in the facial motor nucleus. In this brief review, we describe research from our lab which indicates that the reversal of atrophy in this injury model is dependent on normal cellular immunity. The role of T cells in this unique form of neuroplasticity following injury and in brain aging, are discussed. The potential role of yet undiscover intrinsic actions of recombination activating genes in the brain are considered. Further research using the facial nerve reinjury model could identify molecular signals involved in neuroplasticity, and lead to new ways to stimulate neuroregenerative processes in neurotrauma and other forms of brain insult and disease.

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A Gene Network Perspective on Axonal Regeneration

Cited by 59 publications

References 73 publications

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo

Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter

Reversal of Neuronal Atrophy: Role of Cellular Immunity in Neuroplasticity and Aging

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