ATF3 Increases the Intrinsic Growth State of DRG Neurons to Enhance Peripheral Nerve Regeneration

Abstract

Peripheral axons of dorsal root ganglion (DRG) neurons, but not their central axons in the dorsal columns, regenerate after injury. However, if the neurons are conditioned by a peripheral nerve injury into an actively growing state, the rate of peripheral axonal growth is accelerated and the injured central axons begin to regenerate. The growth-promoting effects of conditioning injuries have two components, increased axonal growth and a reduced response to inhibitory myelin cues. We have examined which transcription factors activated by peripheral axonal injury may mediate the conditioning effect by regulating expression of effectors that increase the intrinsic growth state of the neurons. Activating transcription factor 3 (ATF3) is a prime candidate because it is induced in all injured DRG neurons after peripheral, but not central, axonal damage. To investigate if ATF3 promotes regeneration, we generated transgenic mice that constitutively express this transcription factor in non-injured adult DRG neurons. The rate of peripheral nerve regeneration was enhanced in the transgenic mice to an extent comparable to that produced by a preconditioning nerve injury. The expression of some growth-associated genes, such as SPRR1A, but not others like GAP-43, was increased in the non-injured neurons. ATF3 increased DRG neurite elongation when cultured on permissive substrates but did not overcome the inhibitory effects of myelin or promote central axonal regeneration in the spinal cord in vivo. We conclude that ATF3 contributes to nerve regeneration by increasing the intrinsic growth state of injured neurons.

Plasticity of DNA methylation in a nerve injury model of pain

“…As expected, a considerable fraction of genes were induced or suppressed in response to SNL, 2,938 (28.5%) in the present study, including genes such as AFT3, A2m, NGF, SOCS3, SOX11, and STAT3, which are known to show expression changes following nerve injury. [14][15][16][17][18] As has been proposed in the past, 19 we found genes in which promoter methylation was associated with gene downregulation (29 genes). However, a similar number of genes (36) were upregulated when the promoter was hypermethylated.…”

Neuronal Nogo-A upregulation does not contribute to ER stress-associated apoptosis but participates in the regenerative response in the axotomized adult retina

“…The injury-induced growth response of RGCs was further analyzed by following gene expression changes of Sprr1A, GAP-43 and ATF3, three important regulators of axonal regeneration in the CNS and the PNS. 25,26 The three growth marker mRNAs increased quickly after injury and peaked at 3-5 days post-optic nerve transection (data not shown). Silencing neuronal Nogo-A in injured retina with AAV2.shRNA-Nogo-A lowered the induction of Sprr1A, GAP-43, and ATF3 mRNA (Figures 6e-g; analysis of variance (ANOVA); *Po0.05; **Po0.01).…”

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

“…1d,e). Furthermore, a broader picture of post-axotomy gene expression profiles and H3K9ac promoter enrichment is depicted by regeneration-associated (Chl1, L1cam, SPRR1a) 18 , axonal growth (ATF3 and Bcl-xL) 19,20 housekeeping (ribosomal unit 18S) genes and axonal structure (NF-L) genes 21 (Fig. 2a,b).…”