title: Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD.
abstract: Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD.
authors.affiliation: Department of Molecular and Cell and Developmental Biology, Institute for Cellular and Molecular Biology and Institute for Neuroscience, University of Texas, Austin, TX 78712, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: McCarthy
authors.forename: Leah
authors.initials: L
authors.lastname: Wetherill
authors.forename: C Ben
authors.initials: CB
authors.lastname: Lovely
authors.forename: Mary E
authors.initials: ME
authors.lastname: Swartz
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Johann K
authors.initials: JK
authors.lastname: Eberhart
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002972:Cleft Palate / Q000209:etiology / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D059647:Gene-Environment Interaction; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D009432:Neural Crest / Q000002:abnormalities / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015027:Zebrafish / Q000002:abnormalities* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000431:Ethanol; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D058570:TOR Serine-Threonine Kinases; D029961:Zebrafish Proteins
keywords: Alcohol; FAS; Pdgfra; Zebrafish; mTOR