Injured axons in the central nervous system (CNS) of adult mammals are generally unable to regenerate over long distances, which limits functional recovery after a spinal cord injury. Potential mechanisms underlying this regenerative failure include a reduced intrinsic ability to activate the genes and signaling pathways required for axon growth after injury. In addition, extrinsic growth-inhibiting factors associated with extracellular matrix molecules, myelin debris, or fibrotic tissue play a role. Finally, we now recognize that appropriate growth factors are not available in sufficient quantities. Strategies to neutralize or attenuate major extrinsic inhibitors of axon growth have only limited effects on regeneration, but their efficacy is greatly enhanced when combined with activation of the intrinsic growth state of neurons.
For example, inhibition of PTEN, an intrinsic suppressor of axon growth, results in significant axon regeneration. In combination with factors such as CNTF and SOCS3 deletion or with the intracellular messenger cAMP, it enables some nerve cells, such as retinal ganglion cells, to regenerate axons over the entire length of the injured tract. In contrast to CNS neurons, peripheral sensory and motor neurons spontaneously display extensive growth after peripheral axon injury, accompanied by the activation of regeneration-associated genes (RAGs). These RAGs act as a coordinated network, with their expression regulated by a central group of transcription factors (TFs) during peripheral nerve regeneration. Manipulation of individual TFs, such as STAT3 and Sox11, results in different levels of axon growth in the CNS.
The effects of TFs on their target pathways are combinatorial and form tiered regulatory networks that require precise control of timing, dosage, and context. Analysis of transcriptional networks from gene expression data provides an efficient method for identifying key regulators of biological processes. A model of TF networks originally proposed by the ENCODE consortium describes a hierarchical, pyramid-like structure. At the apex are a few master regulators that control the expression of most other TFs, which in turn regulate target genes. Using such models and newly generated data, the hierarchical interactions of TFs can be analyzed to identify potential key regulators of intrinsic axon regeneration.
A paper published in Nature Communications in 2022 now shows that the RE1-silencing transcription factor (REST; neuron-restrictive silencer factor) as a negative regulator inhibits the activation of regeneration-associated TFs such as Jun, STAT3, Sox11, SMAD1 and ATF3. In adult mice with cell-specific deletion of REST or expression of a dominant-negative REST mutant, improved regeneration of the corticospinal tract after spinal cord injury or of the optic nerve after contusion was observed. Successful regeneration was associated with upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells.
The present results highlight the central role of REST as a master repressor of the intrinsic regeneration program in the CNS and demonstrate the utility of a systems biology approach using integrative genomics and bioinformatics for regeneration research.
Reference:
Cheng Y, Yin Y, Zhang A, Bernstein AM, ... Goldberg JL, He Z, Woolf CJ, Sofroniew MV, Benowitz LI, Geschwind DH (2022) Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice. Nature Communications 13:4418
Image credit: iStock/Mongkolchon Akesin
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