Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure.
Alcohol is a teratogen that induces a variety of abnormalities including brain and facial defects [Jones, K. & Smith, D. (1973) Lancet 2, 999-1001], with the exact nature of the deficit depending on the time and magnitude of the dose of ethanol to which developing fetuses are exposed. In addition to abnormal facial structures, ethanol-treated embryos exhibit a highly characteristic pattern of cell death. Dying cells are observed in the premigratory and migratory neural crest cells that normally populate most facial structures. The observation that blocking Sonic hedgehog (Shh) signaling results in similar craniofacial abnormalities prompted us to examine whether there was a link between this aspect of fetal alcohol syndrome and loss of Shh. We demonstrate that administration of ethanol to chick embryos results in a dramatic loss of Shh, as well as a loss of transcripts involved in Shh signaling pathways. In contrast, other signaling molecules examined do not demonstrate such dramatic changes. Furthermore, we demonstrate that both the ethanol-induced cranial neural crest cell death and the associated craniofacial growth defect can be rescued by application of Shh. These data suggest that craniofacial anomalies resulting from fetal alcohol exposure are caused at least partially by loss of Shh and subsequent neural crest cell death.
Division of Biology 139-74, California Institute of Technology, Pasadena, CA 91125, USA. ahlgren@caltech.edu
Sara C
SC
Ahlgren
Vijaya
V
Thakur
Marianne
M
Bronner-Fraser
D000818:Animals; D019521:Body Patterning; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001921:Brain / Q000196:embryology; D016923:Cell Death; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics; D015870:Gene Expression; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins; D009432:Neural Crest / Q000187:drug effects* / Q000196:embryology; D000072079:Patched Receptors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D015398:Signal Transduction; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C509239:SHH protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; C525822:bmp7.1 protein, Xenopus; C525826:bmp7a protein, zebrafish; C491021:smo protein, zebrafish; D051524:Fibroblast Growth Factor 8; D000431:Ethanol; D005346:Fibroblast Growth Factors