The Francis Crick Institute
Browse

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

Download (2.9 MB)
journal contribution
posted on 2022-04-27, 09:41 authored by Matthew RJ Mason, Susan van Erp, Kim Wolzak, Axel Behrens, Gennadij Raivich, Joost Verhaagen
The regeneration-associated gene (RAG) expression program is activated in injured peripheral neurons after axotomy and enables long-distance axon re-growth. Over 1000 genes are regulated, and many transcription factors are upregulated or activated as part of this response. However, a detailed picture of how RAG expression is regulated is lacking. In particular the transcriptional targets and specific functions of the various transcription factors are unclear. Jun was the first regeneration-associated transcription factor identified and the first shown to be functionally important. Here we fully define the role of Jun in the RAG expression program in regenerating facial motor neurons. At 1, 4, and 14 days after axotomy, Jun upregulates 11%, 23% and 44% of the RAG program, respectively. Jun functions relevant to regeneration include cytoskeleton production, metabolic functions and cell activation, and the down-regulation of neurotransmission machinery. In silico analysis of promoter regions of Jun targets identifies stronger over-representation of AP1-like sites than CRE-like sites, although CRE sites were also over-represented in regions flanking AP1 sites. Strikingly, in motor neurons lacking Jun, an alternative SRF-dependent gene expression program is initiated after axotomy. The promoters of these newly expressed genes exhibit over-representation of CRE sites in regions near to SRF target sites. This alternative gene expression program includes plasticity-associated transcription factors, and leads to an aberrant early increase in synapse density on motor neurons. Jun thus has the important function in the early phase after axotomy of pushing the injured neuron away from a plasticity response and towards a regenerative phenotype.

Funding

Crick (Grant ID: 10039, Grant title: Behrens FC001039)

History

Usage metrics

    The Francis Crick Institute

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC