RGD Reference Report - Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. - Rat Genome Database

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Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.

Authors: Iskandar, BJ  Rizk, E  Meier, B  Hariharan, N  Bottiglieri, T  Finnell, RH  Jarrard, DF  Banerjee, RV  Skene, JH  Nelson, A  Patel, N  Gherasim, C  Simon, K  Cook, TD  Hogan, KJ 
Citation: Iskandar BJ, etal., J Clin Invest. 2010 May;120(5):1603-16. doi: 10.1172/JCI40000. Epub 2010 Apr 26.
RGD ID: 10054082
Pubmed: PMID:20424322   (View Abstract at PubMed)
PMCID: PMC2860927   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI40000   (Journal Full-text)

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
axon regeneration involved_inIMP 10054082; 10054082PMID:20424322BHF-UCL 
cellular response to nitric oxide involved_inIDA 10054082PMID:20424322BHF-UCL 
folic acid metabolic process involved_inIDA 10054082PMID:20424322BHF-UCL 
methionine biosynthetic process involved_inIDA 10054082PMID:20424322BHF-UCL 
response to axon injury involved_inIDA 10054082PMID:20424322BHF-UCL 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dihydrofolate reductase activity enablesIDA 10054082PMID:20424322BHF-UCL 
methionine synthase activity enablesIDA 10054082PMID:20424322BHF-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Dhfr  (dihydrofolate reductase)
Mtr  (5-methyltetrahydrofolate-homocysteine methyltransferase)

Additional Information