Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny

Nirav J. Patel, Kirk J. Hogan, Elias Rizk, Krista Stewart, Andy Madrid, Sivan Vadakkadath Meethal, Reid Alisch, Laura Borth, Ligia A. Papale, Solomon Ondoma, Logan R. Gorges, Kara Weber, Wendell Lake, Andrew Bauer, Nithya Hariharan, Thomas Kuehn, Thomas Cook, Sunduz Keles, Michael A. Newton, Bermans J. Iskandar

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8 Scopus citations


Folate supplementation in F0 mating rodents increases regeneration of injured spinal axons in vivo in 4 or more generations of progeny (F1–F4) in the absence of interval folate administration to the progeny. Transmission of the enhanced regeneration phenotype to untreated progeny parallels axonal growth in neuron culture after in vivo folate administration to the F0 ancestors alone, in correlation with differential patterns of genomic DNA methylation and RNA transcription in treated lineages. Enhanced axonal regeneration phenotypes are observed with diverse folate preparations and routes of administration, in outbred and inbred rodent strains, and in two rodent genera comprising rats and mice, and are reversed in F4–F5 progeny by pretreatment with DNA demethylating agents prior to phenotyping. Uniform transmission of the enhanced regeneration phenotype to progeny together with differential patterns of DNA methylation and RNA expression is consistent with a non-Mendelian mechanism. The capacity of an essential nutritional co-factor to induce a beneficial transgenerational phenotype in untreated offspring carries broad implications for the diagnosis, prevention, and treatment of inborn and acquired disorders.

Original languageEnglish (US)
Pages (from-to)2048-2071
Number of pages24
JournalMolecular Neurobiology
Issue number4
StatePublished - Apr 1 2020

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience


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