Genes and miRNAs as Hurdles and Promoters of Corticospinal Tract Regeneration in Spinal Cord Injury

Frontiers in Cell and Developmental Biology, 2021 · DOI: 10.3389/fcell.2021.748911 · Published: October 15, 2021

Simple Explanation

Spinal cord injury disrupts communication between the brain and body, leading to loss of motor and sensory function. A major challenge is the limited ability of damaged nerve fibers to regenerate in the central nervous system. Researchers are exploring ways to stimulate nerve regrowth by understanding the genetic programs that control axon development and regeneration. Key genes, transcription factors, and miRNAs are being investigated for their role in promoting or hindering this process. The review discusses how reactivating developmental axon growth programs in adult neurons could be a potential therapeutic approach to promote regeneration after spinal cord injury.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
Corticospinal motor neurons (CSMNs) exhibit limited regeneration ability after spinal cord injury compared to other pathways in the central nervous system.
2
Forced expression of certain transcription factors like KLF7, STAT3, and SOX11 can promote sprouting and axonal regeneration of CSMNs after SCI in animal models.
3
MicroRNAs (miRNAs) play a role in regulating axon regeneration, inflammation, apoptosis, and remyelination after SCI, with some miRNAs like miR-20a and miR-128 promoting axon outgrowth.

Research Summary

The review highlights the complexity of the genetic system involved in central axon regeneration after SCI. Some genes active during development, such as KLF7, SOX11 and STAT3, are potential therapeutic targets in adulthood. The environment after SCI is hostile and inhibitory mechanisms limit the intrinsic regenerative attempt of CSMN axons. Combined therapeutic approaches limiting these inhibitory mechanisms and activating transcriptional programs may be needed. Modern experimental approaches, including multi-layer omics and genetic reprogramming, will allow providing new insights into how axonal regrowth is promoted, possibly even exploiting the silenced developmental processes.

Practical Implications

Therapeutic Targets

Identifies specific genes, transcription factors, and miRNAs (e.g., KLF7, STAT3, SOX11, miR-20a) as potential therapeutic targets for promoting axon regeneration after SCI.

Combined Therapies

Suggests that combined therapeutic approaches that both limit inhibitory mechanisms and activate transcriptional programs in axotomized neurons may be necessary for substantial axonal regrowth.

Future Research Directions

Emphasizes the need for further investigation of the transcriptional and structural remodeling occurring within the sensory-motor cortex after CSMN axotomy to gain a more complete understanding of the regenerative process.

Study Limitations

1
The review focuses primarily on the genetic aspects of corticospinal tract regeneration, with less emphasis on other factors such as inflammation and glial scarring.
2
The review acknowledges that the hostile environment after SCI and inhibitory mechanisms can limit axon regeneration, but does not fully explore these mechanisms.
3
The long-term functional outcomes of axonal regrowth achieved through genetic manipulation are not fully understood, as demonstrated by the reduced dexterity observed with SOX11 overexpression.

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