The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons

Mol Cell Neurosci, 2015 · DOI: 10.1016/j.mcn.2015.08.008 · Published: September 1, 2015

Simple Explanation

This study identifies HHEX, a tumor suppressor, as an inhibitor of axon growth in CNS neurons. HHEX limits axon growth through transcriptional repression. HHEX is found in adult CNS neurons but not in early postnatal neurons or DRG neurons. Ectopic expression of HHEX reduces axon growth in postnatal and DRG neurons. The research indicates that tumor suppressor genes may inhibit axonal growth, contributing to the reduced regenerative capacity observed in mature CNS neurons.

Study Duration

Not specified

Participants

Sprague Dawley rat pups (P3-P5), Adult Mice

Evidence Level

Not specified

Key Findings

1
HHEX acts as a potent suppressor of axon growth when overexpressed in CNS neurons.
2
HHEX inhibits axon growth through a mechanism of transcriptional repression.
3
Ectopic expression of full-length HHEX reduces the regenerative capacity of DRG neurons.

Research Summary

This study identifies HHEX as a suppressor of axon growth when overexpressed in CNS neurons, acting through transcriptional repression to reduce axon initiation and extension without affecting cell viability. HHEX is endogenously expressed in the nuclei of CNS neurons, including CST neurons after axotomy, while peripheral DRG neurons express much lower levels. Forced expression of HHEX in early postnatal cortical neurons or DRG neurons results in defects in both axon formation and extension, supporting the hypothesis that HHEX may limit axon growth in CNS neurons.

Practical Implications

Therapeutic target

Neutralizing TFs like HHEX that repress transcription by occupying pro-regenerative loci may complement the overexpression approach to enhance axon growth.

Understanding regeneration

Clarifying the potential interactions of HHEX with JUN and/or MYC in the context of axon growth, represent important directions for future research.

Cancer-related factors

Further study of factors implicated in cancer biology may be a productive means to identify new regulators of axon growth.

Study Limitations

1
The identity of HHEX target genes in neurons remains unclear.
2
Direct assays of transcriptional activity are needed to confirm HHEX’s transcriptional mode of activity.
3
Comparison between immunohistochemistry experiments must be made cautiously.

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