The Jun-dependent axon regeneration gene program: Jun promotes regeneration over plasticity

Area of Science:

• Neuroscience
• Molecular Biology
• Regenerative Medicine

Background:

• Peripheral nerve injury triggers a regeneration-associated gene (RAG) expression program to promote axon regrowth.
• While many transcription factors are involved, their specific roles and regulatory targets within the RAG program remain unclear.
• Jun was the first identified regeneration-associated transcription factor, but its comprehensive role is not fully understood.

Purpose of the Study:

• To fully define the role of Jun in the RAG expression program in regenerating facial motor neurons.
• To identify the transcriptional targets and specific functions of Jun during neuronal regeneration.
• To investigate the consequences of Jun deficiency on the RAG program and neuronal response to injury.

Main Methods:

• Axotomy of facial motor neurons in vivo.
• Quantitative analysis of RAG gene expression at different time points post-axotomy.
• In silico analysis of promoter regions of Jun target genes.
• Assessment of gene expression programs in Jun-deficient motor neurons.

Main Results:

• Jun upregulates a significant percentage of the RAG program, with increasing contribution over time (11% at 1 day, 23% at 4 days, 44% at 14 days post-axotomy).
• Jun-mediated functions include promoting cytoskeleton production, metabolic activity, cell activation, and downregulating neurotransmission machinery.
• In the absence of Jun, an alternative SRF-dependent gene expression program is activated, characterized by plasticity-associated factors and aberrant synapse formation.

Conclusions:

• Jun is critical for orchestrating the early regenerative response in injured peripheral neurons.
• Jun actively suppresses a plasticity-associated program, directing neurons towards a regenerative phenotype.
• Understanding Jun's regulatory network is key to enhancing neuronal regeneration after injury.