Intrinsic mechanisms controlling axon regeneration

We are studying the mechanisms by which a pro-regenerative state is reprogrammed following axon injury in sensory neurons. We discovered that increased histone acetylation following the nuclear export of HDAC5 is required for axon regeneration in sensory neurons. This study represents a pioneering discovery in the field of axon regeneration, which identified an epigenetic mechanism by which injured neurons transition to a pro-regenerative state. Because epigenetic modifications affect globally, yet specifically a combination of multiple genes, they represent ideal strategies to promote neural repair.

We also discovered a critical role for the transcription factor HIF-1α in axon regeneration. We found that HIF-1α co-coordinates the expression of multiple pro-regenerative genes. Low oxygen levels (hypoxia) can increase HIF-1α levels and we found that acute intermittent hypoxia(AIH) accelerates axon regeneration. Importantly, AIH has been used in human patients and was shown to be a safe and effective treatment strategy to strengthen recovery (such as walking enhancement) in human patients with incomplete chronic spinal cord injury. Our findings thus bring a novel and important contribution to the field of axon regeneration.

This image has an empty alt attribute; its file name is 1.-hif1-image-1024x437.jpeg

Although expression of regeneration-associated genes is essential to activate the axon regeneration program, less is known about the contribution of gene inactivation. We demonstrated that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. This study also provides a better understanding of the transient gene regulatory networks employed by peripheral neurons to promote axon regeneration.

We continue to employ a combination of approaches, including in vitro genetic and drug screens combined with RNAseq and ATACseq studies in defined neuronal populations to understand how a pro-regenerative state can be activated after axon injury.

We also continue our studies on the role of the microtubule cytoskeleton and axonal transport in axon regeneration.

Key publications: