Activating Transcription Factor 3 (ATF3) is a Highly Conserved Pro-regenerative Transcription Factor in the Vertebrate Nervous System

Frontiers in Cell and Developmental Biology, 2022 · DOI: 10.3389/fcell.2022.824036 · Published: March 8, 2022

Regenerative Medicine Neurology Genetics

Simple Explanation

The ability to regenerate nerve tissues varies greatly across different animal species. Some animals, like lampreys and zebrafish, can regenerate their nervous systems after injury, while mammals have limited capacity. By studying the molecular mechanisms behind nerve regeneration in different species, we can identify key factors that promote successful regeneration. Activating transcription factor 3 (ATF3) is one such factor that appears to be conserved across vertebrates. ATF3 is rapidly induced in neurons after nerve injury in multiple species and promotes axon regrowth and regeneration. By studying ATF3, we can better understand the molecular basis of vertebrate CNS regeneration and develop therapeutic strategies for spinal cord injury. This review summarizes the current evidence for ATF3 as a conserved pro-regenerative factor. It explores how ATF3 works with other regeneration-associated genes (RAGs) to activate gene transcription, leading to axonal regrowth. It also discusses the potential of ATF3 as a therapeutic strategy for promoting CNS regeneration after traumatic spinal cord injury (SCI).

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
ATF3 protein is highly conserved across vertebrate species, suggesting it may share similar functions in the nervous system.
2
ATF3 is rapidly induced in the nervous systems of highly regenerative species following traumatic injury, specifically in neuronal cell types.
3
Studies suggest that post-injury ATF3 induction in neurons promotes greater axonal regrowth, regeneration, or sprouting.

Research Summary

This review focuses on ATF3, a transcription factor that is emerging as a conserved pro-regenerative factor across vertebrates, particularly in the nervous system. ATF3 is consistently induced in neurons after nerve injury in various species, suggesting a positive role in neural regeneration. The authors discuss the structural and functional conservation of ATF3 protein across species and its role in promoting neuronal axon regrowth and regeneration. They compare RNA expression data across species with different regenerative abilities, showing that ATF3 is consistently induced in neurons after injury. Genetic studies in mice and zebrafish have shown that ATF3 promotes axon regeneration, while its deletion reduces axon regrowth. The review concludes that ATF3 may be an evolutionarily conserved regulator of neuronal regeneration and that identifying its downstream effectors will be crucial for understanding vertebrate CNS regeneration.

Practical Implications

Therapeutic Target

ATF3 could be a potential therapeutic target for promoting CNS regeneration after traumatic spinal cord injury.

Understanding Regeneration

Identifying downstream effectors of ATF3 will be a critical next step in understanding the molecular basis of vertebrate CNS regeneration.

Combinatorial Therapy

The pre-dimerized cJUN-ATF3 complex may be a viable tool for promoting neural regeneration that could be developed further for preclinical testing.

Study Limitations

1
The normal functions of ATF3 must be considered, along with possible downstream effects of manipulating this transcription factor, and possible routes of administration.
2
Identifying which of ATF3’s binding partners and potential targets are driving its pro-regenerative role in the nervous system is challenging.
3
More studies are needed to fully understand how ATF3 influences regenerative processes beyond its established roles in axon regrowth and regeneration.

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