Abstract
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 downregulation 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.
Highlights
Neurons axotomized by peripheral nerve injury initiate a gene expression program, which facilitates longdistance regeneration in peripheral nerves, but can achieve growth in inhibitory areas such as sites of spinal cord injury [1]
In the case of several transcription factors (TFs) a small number of targets have been identified [8,22,23,24], and an important role for ATF3 in activating regenerative gene transcription was shown in sensory neurons [25], in general, it is not known which regeneration-associated gene (RAG) are regulated by which TF and to what degree, and whether key RAG TFs upregulate other RAG TFs
Jun deletion causes profound differences in gene expression after axotomy Floxed Jun mice crossed with nestin-cre mice, in which Jun is deleted in the central nervous system, and cre-negative littermates received a facial nerve injury
Summary
Neurons axotomized by peripheral nerve injury initiate a gene expression program, which facilitates longdistance regeneration in peripheral nerves, but can achieve growth in inhibitory areas such as sites of spinal cord injury [1]. RAG expression appears to be triggered after peripheral axotomy by a combination of retrograde signals and calcium signaling, leading to the upregulation and/or activation of a considerable number of transcription factors (TFs), including ATF3, Jun, CREB, STAT3, Smad, CEBPD and Klf family factors [4], and is accompanied by epigenetic changes, in particular histone acetylation and increased chromatin accessibility [5,6,7]. In the case of several TFs a small number of targets have been identified [8,22,23,24], and an important role for ATF3 in activating regenerative gene transcription was shown in sensory neurons [25], in general, it is not known which RAGs are regulated by which TF and to what degree, and whether key RAG TFs upregulate other RAG TFs. Little is known about how TFs co-operate in regenerating peripheral neurons. More broadly for most TFs, including Jun, it is not possible to ascribe to them a particular function in the regeneration program
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