The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects

J Comp Neurol. 2007 Jan 10;500(2):368-83. doi: 10.1002/cne.21179.


Folate supplementation prevents up to 70% of human neural tube defects (NTDs), although the precise cellular and metabolic sites of action remain undefined. One possibility is that folate modulates the function of metabolic enzymes expressed in cellular populations involved in neural tube closure. Here we show that the folate metabolic enzyme ALDH1L1 is cell-specifically expressed in PAX3-negative radial glia at the midline of the neural tube during early murine embryogenesis. Midline restriction is not a general property of this branch of folate metabolism, as MTHFD1 displays broad and apparently ubiquitous expression throughout the neural tube. Consistent with previous work showing antiproliferative effects in vitro, ALDH1L1 upregulation during central nervous system (CNS) development correlates with reduced proliferation and most midline ALDH1L1(+) cells are quiescent. These data provide the first evidence for localized differences in folate metabolism within the early neural tube and suggest that folate might modulate proliferation via effects on midline Aldh1l1(+) cells. To begin addressing its role in neurulation, we analyzed a microdeletion mouse strain lacking Aldh1l1 and observed neither increased failure of neural tube closure nor detectable proliferation defects. Although these results indicate that loss-of-function Aldh1l1 mutations do not impair these processes in mice, the specific midline expression of ALDH1L1 and its ability to dominantly suppress proliferation in a folate responsive manner may suggest that mutations contributing to disease are gain-of-function, rather than loss-of-function. Moreover, a role for loss-of-function mutations in human NTDs remains possible, as Mthfr null mice do not develop NTDs even though MTHFR mutations increase human NTD risk.

Publication types

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

MeSH terms

  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Central Nervous System / abnormalities*
  • Central Nervous System / enzymology*
  • Central Nervous System / physiopathology
  • Disease Models, Animal
  • Female
  • Folic Acid / metabolism*
  • Gene Expression Regulation, Developmental / genetics
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Isoenzymes / genetics*
  • Isoenzymes / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation / genetics
  • Neural Tube Defects / enzymology*
  • Neural Tube Defects / genetics
  • Neural Tube Defects / physiopathology
  • Neuroglia / cytology
  • Neuroglia / enzymology
  • Neurons / cytology
  • Neurons / enzymology
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism
  • Retinal Dehydrogenase
  • Stem Cells / cytology
  • Stem Cells / enzymology
  • Up-Regulation / physiology


  • Isoenzymes
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors
  • Pax3 protein, mouse
  • Folic Acid
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase