Neural crest development in fetal alcohol syndrome

Birth Defects Res C Embryo Today. 2014 Sep;102(3):210-20. doi: 10.1002/bdrc.21078. Epub 2014 Sep 15.


Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability. Some affected individuals possess distinctive craniofacial deficits, but many more lack overt facial changes. An understanding of the mechanisms underlying these deficits would inform their diagnostic utility. Our understanding of these mechanisms is challenged because ethanol lacks a single receptor when redirecting cellular activity. This review summarizes our current understanding of how ethanol alters neural crest development. Ample evidence shows that ethanol causes the "classic" fetal alcohol syndrome (FAS) face (short palpebral fissures, elongated upper lip, deficient philtrum) because it suppresses prechordal plate outgrowth, thereby reducing neuroectoderm and neural crest induction and causing holoprosencephaly. Prenatal alcohol exposure (PAE) at premigratory stages elicits a different facial appearance, indicating FASD may represent a spectrum of facial outcomes. PAE at this premigratory period initiates a calcium transient that activates CaMKII and destabilizes transcriptionally active β-catenin, thereby initiating apoptosis within neural crest populations. Contributing to neural crest vulnerability are their low antioxidant responses. Ethanol-treated neural crest produce reactive oxygen species and free radical scavengers attenuate their production and prevent apoptosis. Ethanol also significantly impairs neural crest migration, causing cytoskeletal rearrangements that destabilize focal adhesion formation; their directional migratory capacity is also lost. Genetic factors further modify vulnerability to ethanol-induced craniofacial dysmorphology and include genes important for neural crest development, including shh signaling, PDFGA, vangl2, and ribosomal biogenesis. Because facial and brain development are mechanistically and functionally linked, research into ethanol's effects on neural crest also informs our understanding of ethanol's CNS pathologies.

Keywords: apoptosis; calcium signaling; craniofacial; fetal alcohol spectrum disorders; neural crest; sonic hedgehog.

Publication types

  • Review

MeSH terms

  • Alcohol Drinking / adverse effects
  • Animals
  • Apoptosis / drug effects
  • Cell Movement / drug effects
  • Disease Models, Animal
  • Ethanol / administration & dosage
  • Ethanol / adverse effects
  • Female
  • Fetal Alcohol Spectrum Disorders / etiology
  • Fetal Alcohol Spectrum Disorders / pathology*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Neural Crest / drug effects
  • Neural Crest / pathology*
  • Neurogenesis / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects / etiology
  • Prenatal Exposure Delayed Effects / pathology
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Hedgehog Proteins
  • beta Catenin
  • Ethanol