title: Calcium-mediated repression of β-catenin and its transcriptional signaling mediates neural crest cell death in an avian model of fetal alcohol syndrome.
abstract: Fetal alcohol syndrome (FAS) is a common birth defect in many societies. Affected individuals have neurodevelopmental disabilities and a distinctive craniofacial dysmorphology. These latter deficits originate during early development from the ethanol-mediated apoptotic depletion of cranial facial progenitors, a population known as the neural crest. We showed previously that this apoptosis is caused because acute ethanol exposure activates G-protein-dependent intracellular calcium within cranial neural crest progenitors, and this calcium transient initiates the cell death. The dysregulated signals that reside downstream of ethanol's calcium transient and effect neural crest death are unknown. Here we show that ethanol's repression of the transcriptional effector β-catenin causes the neural crest losses. Clinically relevant ethanol concentrations (22-78 mM) rapidly deplete nuclear β-catenin from neural crest progenitors, with accompanying losses of β-catenin transcriptional activity and downstream genes that govern neural crest induction, expansion, and survival. Using forced expression studies, we show that β-catenin loss of function (via dominant-negative T cell transcription factor [TCF]) recapitulates ethanol's effects on neural crest apoptosis, whereas β-catenin gain-of-function in ethanol's presence preserves neural crest survival. Blockade of ethanol's calcium transient using Bapta-AM normalizes β-catenin activity and prevents the neural crest losses, whereas ionomycin treatment is sufficient to destabilize β-catenin. We propose that ethanol's repression of β-catenin causes the neural crest losses in this model of FAS. β-Catenin is a novel target for ethanol's teratogenicity. β-Catenin/Wnt signals participate in many developmental events and its rapid and persistent dysregulation by ethanol may explain why the latter is such a potent teratogen.
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Flentke
authors.forename: Ana
authors.initials: A
authors.lastname: Garic
authors.forename: Ed
authors.initials: E
authors.lastname: Amberger
authors.forename: Marcos
authors.initials: M
authors.lastname: Hernandez
authors.forename: Susan M
authors.initials: SM
authors.lastname: Smith
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D002642:Chick Embryo; D002645:Chickens; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009432:Neural Crest / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D051176:beta Catenin; D000431:Ethanol; D002118:Calcium