Transcription factor network analysis offers hope of CNS axon regeneration

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Axons injured in the central nervous system of adult mammals generally cannot regenerate over long distances, which limits functional recovery after central nervous system injury, but also the hopes of recovery in ALS patients. enter image description here Source: Can injured adult CNS axons regenerate by recapitulating development? Brett J. Hilton, Frank Bradke

The potential mechanisms underlying regeneration failure in the mature central nervous system include factors intrinsic and extrinsic to the central nervous system.

The presence of extrinsic growth repellent factors is associated with certain molecules in the extracellular matrix, myelin debris or fibrous tissue, and the limited availability of suitable growth factors.

Strategies to neutralize or attenuate the major extrinsic inhibitors of axonal growth have limited effects on regeneration.

Suppression of PTEN, an intrinsic suppressor of axonal growth, induces appreciable axonal regeneration, and when this suppression is combined with other factors, it allows a significant percentage of retinal ganglion cells to regrow their axons along their entire length. optic nerve.

PTEN is associated with cancer, non-cancerous neoplasms, brain function, autism, and cell regeneration. The strong link of PTEN with inhibition of cell growth is being investigated as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have been shown to enable nerve regeneration in mice.

Nevertheless, more work is needed to identify the main regulators of axon regeneration in the central nervous system. Unlike their central nervous system counterparts, sensory and motor neurons of the peripheral nervous system, they spontaneously display potent growth in response to peripheral axonal injury, which is accompanied by the activation of key genes associated with regeneration (RAG ).

Scientists predicted that the expression of this RAG network would be controlled by a central group transcription factor during the regeneration of peripheral nerves. Indeed, the manipulation of transcription factors at the heart of this network, such as STAT, members of the KLF and Sox family, leads to the growth of axons of the central nervous system.

The scientists then used a System Biology type approach. Enter image description here Systems biology is generally defined in opposition to the traditional so-called reductionist paradigm. The reductionist approach has succeeded in identifying most of the biological components and many interactions but, unfortunately, offers no convincing concept or method for understanding how the properties of the system emerge. Pluralism of causes and effects in biological networks is best addressed by observing, through quantitative measurements, several components simultaneously and by rigorous integration of data with mathematical models (Sauer et al.).

Here, those scientists integrated several existing and newly generated datasets to characterize hierarchical interactions of transcription factors in order to identify regulators that would be potentially associated with axon regeneration.

By comparing gene expression in conditions such as damage to the central nervous system, with behavior in the peripheral nervous system or even in the central nervous system when it has been subjected to powerful pro-regenerative treatments, the scientists emitted the 'hypothesis that they could identify the main transcription factors regulating intrinsic regeneration programs.

The authors began with a network analysis approach based on mutual information to characterize the transcriptional regulatory network formed by transcription factors associated with regeneration in several independent data sets.

They identified a basic three-level subnet of five interconnected transcription factors, composed of Jun, STAT, Sox, SMAD, and ATF, which is remarkably preserved in several models of peripheral nervous system injury and at different time scales. .

Remarkably, scientists have observed a similar, multi-layered and highly interconnected transcription factor structure in central nervous system neurons after genetic and pharmacological treatments that enhance regeneration.

However, in the central nervous system, subnet associated with regeneration and its higher level hierarchical structure have a less interconnected and less hierarchical structure.

Their analyzes identified the RE1-silencing transcription factor (REST), a widely studied regulator of neural development and expression of specific neuronal genes, as playing a potentially important role in suppressing regeneration of the central nervous system. Yet REST expression is strongly correlated with increased longevity. REST levels are highest in the brains of people who have lived to be 90 to 100 years old and who have remained cognitively intact. It is believed that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces expression of stress response genes.

Bioinformatics analyzes have shown that REST is present at the top of a degenerate transcription factor network in the central nervous system, but absent in the peripheral nervous system and in neurons of the central nervous system with improved regenerative potential, both in the optic nerve and spinal cord.

Their findings suggest that REST acts as a potential upstream transcriptional repressor, limiting the interactions of basic regenerative transcription factors to drive RAG expression and the intrinsic growth capacity of central nervous system neurons.

This hypothesis was supported by the transcriptomic analysis of REST-depleted central nervous system-injured neurons which exhibited enhanced expression of a network of regeneration-associated genes driven by several basic transcription factors known to promote regeneration.

To further validate their bioinformatics predictions, the scientists investigated the effects of REST neutralization on regeneration in two different models of central nervous system injury: in vivo optic nerve crush and complete spinal cord injury. In both cases, the neutralization of REST resulted in increased regeneration.

These results demonstrate how a multistage biological systems analysis coupled with substantial experimental validation in vitro and in vivo provides a framework for the discovery of central nervous system repair drivers and implicate REST as a novel regulator of regeneration of axons of the central nervous system.

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