Folate-dependent methylation of septins governs ciliogenesis during neural tube closure

FASEB J. 2017 Aug;31(8):3622-3635. doi: 10.1096/fj.201700092R. Epub 2017 Apr 21.

Abstract

Periconception maternal folic acid (vitamin B9) supplementation can reduce the prevalence of neural tube defects (NTDs), although just how folates benefit the developing embryo and promote closing of the neural tube and other morphologic processes during development remains unknown. Folate contributes to a 1-carbon metabolism, which is essential for purine biosynthesis and methionine recycling and affects methylation of DNA, histones, and nonhistone proteins. Herein, we used animal models and cultured mammalian cells to demonstrate that disruption of the methylation pathway mediated by folate compromises normal neural tube closure (NTC) and ciliogenesis. We demonstrate that the embryos with NTD failed to adequately methylate septin2, a key regulator of cilium structure and function. We report that methylation of septin2 affected its GTP binding activity and formation of the septin2-6-7 complex. We propose that folic acid promotes normal NTC in some embryos by regulating the methylation of septin2, which is critical for normal cilium formation during early embryonic development.-Toriyama, M., Toriyama, M., Wallingford, J. B., Finnell, R. H. Folate-dependent methylation of septins governs ciliogenesis during neural tube closure.

Keywords: epigenetics; folate transport; neural tube defect; septin2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cilia / physiology*
  • Dactinomycin / analogs & derivatives
  • Embryo, Mammalian / metabolism*
  • Embryo, Nonmammalian / metabolism*
  • Embryonic Development / physiology
  • Folic Acid / metabolism*
  • Gene Expression Regulation, Developmental / physiology
  • HEK293 Cells
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Methylation
  • Mice
  • Neural Tube / physiology*
  • Neural Tube Defects / etiology
  • Plasmids
  • Septins / metabolism*
  • Signal Transduction
  • Xenopus / embryology

Substances

  • Hedgehog Proteins
  • methylated actinomycin D
  • Dactinomycin
  • Folic Acid
  • Septins