{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T09:17:06Z","timestamp":1778404626386,"version":"3.51.4"},"reference-count":60,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["U54 AA019765"],"award-info":[{"award-number":["U54 AA019765"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Ethanol is a teratogen affecting numerous regions of the developing nervous system. The present study was undertaken to ascertain whether ethanol independently disrupts distinct signaling pathways or rather disrupts interactive pathways that regulate development of ethanol\u2010sensitive tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Zebrafish embryos were exposed to ethanol in the absence or presence of <jats:italic>aldh1a3<\/jats:italic> or <jats:italic>Shh<\/jats:italic> morpholino oligonucleotides (MOs), which disrupt retinoic acid (RA) or sonic hedgehog (Shh) function, respectively. Morphological analysis of ocular or midbrain\u2013hindbrain boundary (MHB) development was conducted, and the ability to rescue ethanol and MO\u2010induced phenotypes was assessed. In situ hybridization was used to analyze <jats:italic>Pax6a<\/jats:italic> expression during ocular development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Chronic ethanol exposure, or combined ethanol and MO treatment, results in perturbed MHB formation and microphthalmia. While RA can rescue the MHB phenotype following ethanol combined with either MO, <jats:italic>Shh<\/jats:italic> mRNA is unable to rescue the disrupted MHB with combined ethanol and <jats:italic>aldh1a3<\/jats:italic> MO treatment. RA also is unable to rescue microphthalmia induced by ethanol and <jats:italic>Shh<\/jats:italic> MO.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These studies demonstrate that while reduction of either RA or Shh signaling produces the same disruption of MHB or ocular development, that can be phenocopied using ethanol combined with either MO, RA overexpression can only rescue disrupted MHB, but not microphthalmia, in combined subthreshold <jats:italic>Shh<\/jats:italic> MO and ethanol. Our data suggest that MHB development may involve crosstalk between RA and Shh signaling, while ocular development depends on RA and Shh signaling that both are targets of ethanol in fetal alcohol spectrum disorders but do not depend on a mechanism involving crosstalk. 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