Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.
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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.
Central Nervous System
DNA Modification Methylases
In Situ Hybridization
Published Version (Please cite this version)10.1172/JCI40000
Publication InfoIskandar, Bermans J; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H; ... Hogan, Kirk J (2010). Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest, 120(5). pp. 1603-1616. 10.1172/JCI40000. Retrieved from https://hdl.handle.net/10161/4324.
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Associate Research Professor of Neurobiology
Extension of long axons is essential for the formation of connections in the developing nervous system, and for effective regeneration of pathways interrupted by traumatic injury, stroke, or other insults in the adult CNS. This laboratory is exploring how changes in genes expression during development alter the ability of neurons to support long axon extension, and the extent to which the re-activation of critical genes limits regeneration in the adult CNS. Global gene expression p