Ethanol exposure affects gene expression in the embryonic organizer and reduces retinoic acid levels

Ronit Yelin, Racheli Ben Haroush Schyr, Hadas Kot, Sharon Zins, Ayala Frumkin, Graciela Pillemer, Abraham Fainsod*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Fetal Alcohol Spectrum Disorder (FASD) is a set of developmental malformations caused by alcohol consumption during pregnancy. Fetal Alcohol Syndrome (FAS), the strongest manifestation of FASD, results in short stature, microcephally and facial dysmorphogenesis including microphthalmia. Using Xenopus embryos as a model developmental system, we show that ethanol exposure recapitulates many aspects of FAS, including a shortened rostro-caudal axis, microcephally and microphthalmia. Temporal analysis revealed that Xenopus embryos are most sensitive to ethanol exposure between late blastula and early/mid gastrula stages. This window of sensitivity overlaps with the formation and early function of the embryonic organizer, Spemann's organizer. Molecular analysis revealed that ethanol exposure of embryos induces changes in the domains and levels of organizer-specific gene expression, identifying Spemann's organizer as an early target of ethanol. Ethanol also induces a defect in convergent extension movements that delays gastrulation movements and may affect the overall length. We show that mechanistically, ethanol is antagonistic to retinol (Vitamin A) and retinal conversion to retinoic acid, and that the organizer is active in retinoic acid signaling during early gastrulation. The model suggests that FASD is induced in part by an ethanol-dependent reduction in retinoic acid levels that are necessary for the normal function of Spemann's organizer.

Original languageAmerican English
Pages (from-to)193-204
Number of pages12
JournalDevelopmental Biology
Volume279
Issue number1
DOIs
StatePublished - 1 Mar 2005

Bibliographical note

Funding Information:
We wish to thank Enrique Amaya for teaching us the transgenic procedure. We thank Eddy De Robertis, Jacqueline Deschamps, Yoshiki Sasai, Tomas Pieler and Thomas Hollemann for plasmids and probes. We are indebted to Herbert Steinbeisser and Yosef Gruenbaum for critically reading the manuscript. This work was funded in part by grants from the March of Dimes, Birth Defects Foundation and the Israel Cancer Research Fund to AF.

Keywords

  • Cyp26
  • Embryonic organizer
  • FAS
  • FASD
  • Fetal alcohol syndrome
  • Gastrula
  • Retinol
  • Vitamin A
  • Xenopus
  • gsc

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