Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in Adult Central Nervous System

Cell Rep, 2016 · DOI: 10.1016/j.celrep.2016.03.029 · Published: April 12, 2016

Neurology Genetics Regenerative Medicine & Stem Cells

Simple Explanation

This research investigates how STAT3, a protein involved in cell communication and gene regulation, affects the regrowth of nerve fibers (axons) in the adult central nervous system (CNS) after injury. The study found that STAT3 moves to both the nucleus and mitochondria of nerve cells upon stimulation. The study showed that STAT3's gene regulating function is essential for axon regrowth, while its presence in mitochondria boosts cell energy and further enhances regrowth. MEK, another protein, regulates STAT3's location and function, and this effect is amplified by deleting Pten, leading to significant axon regrowth in the optic pathway and spinal cord of mice. These findings highlight the importance of STAT3's gene-regulating activity for nerve cells in the CNS, with mitochondrial STAT3 playing a supportive role. They also emphasize the critical role of MEK in enhancing various STAT3 functions and promoting axon regrowth.

Study Duration

Not specified

Participants

Mice (C57BL/6J, Ptenf/f, Stat3f/f, R26 loxP-stop-loxP-tdTomato, Cox10f/f and Ptenf/f;R26-tdTomato, Stat3f/f;R26-tdTomato)

Evidence Level

Not specified

Key Findings

1
STAT3 translocates to both the nucleus and mitochondria in mature CNS neurons upon cytokine stimulation, suggesting distinct roles in different cellular compartments.
2
STAT3's transcriptional function is indispensable for CNS axon regrowth, while mitochondrial STAT3 enhances bioenergetics and further potentiates regrowth, indicating a cooperative effect.
3
MEK regulates STAT3's localization, functions, and growth-promoting effects, and this effect is further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord.

Research Summary

This study investigates the role of STAT3, a transcription factor, in axon regrowth in the mature central nervous system (CNS). It demonstrates that STAT3 translocates to both the nucleus and mitochondria upon cytokine stimulation. The research shows that STAT3's transcriptional function is crucial for CNS axon regrowth, while mitochondrial STAT3 enhances bioenergetics and further promotes regrowth. MEK regulates STAT3's functions, with Pten deletion further enhancing axon regrowth. The findings highlight the importance of STAT3's transcriptional activity and the ancillary role of mitochondrial STAT3 in CNS neurons, emphasizing the critical contribution of MEK in enhancing STAT3 functions and axon regrowth.

Practical Implications

Therapeutic Target Identification

STAT3's divergent functions and its regulation by MEK could be targeted for promoting functional axon regrowth in CNS injuries.

Combinatorial Therapies

Combining STAT3 activation with MEK modulation and Pten deletion may lead to more effective strategies for promoting axon regeneration and sprouting.

Understanding CNS Repair Mechanisms

Delineating the specific roles of nuclear and mitochondrial STAT3 can provide a clearer understanding of the molecular mechanisms underlying CNS axon regeneration.

Study Limitations

1
The study primarily focuses on RGC axon regeneration and CST sprouting in mice, and the findings may not be directly applicable to other neuronal types or species.
2
The precise mechanisms by which mitochondrial STAT3 enhances bioenergetics and the specific mitochondrial functions modulated by STAT3 remain to be fully elucidated.
3
The long-term effects and potential side effects of simultaneously modulating PTEN, STAT3, and MEK in neurons need further investigation.

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