{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T22:28:46Z","timestamp":1773700126550,"version":"3.50.1"},"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R01AA011085"],"award-info":[{"award-number":["R01AA011085"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007890","name":"University of North Carolina at Chapel Hill","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Prenatal alcohol exposure (PAE) causes cognitive impairment and a distinctive craniofacial dysmorphology, due in part to apoptotic losses of the pluripotent cranial neural crest cells (CNCs) that form facial bones and cartilage. We previously reported that PAE rapidly represses expression of &gt;70 ribosomal proteins (padj = 10-E47). Ribosome dysbiogenesis causes nucleolar stress and activates p53-MDM2-mediated apoptosis. Using primary avian CNCs and the murine CNC line O9-1, we tested whether nucleolar stress and p53-MDM2 signaling mediates this apoptosis. We further tested whether haploinsufficiency in genes that govern ribosome biogenesis, using a blocking morpholino approach, synergizes with alcohol to worsen craniofacial outcomes in a zebrafish model. In both avian and murine CNCs, pharmacologically relevant alcohol exposure (20mM, 2hr) causes the dissolution of nucleolar structures and the loss of rRNA synthesis; this nucleolar stress persisted for 18-24hr. This was followed by reduced proliferation, stabilization of nuclear p53, and apoptosis that was prevented by overexpression of MDM2 or dominant-negative p53. In zebrafish embryos, low-dose alcohol or morpholinos directed against ribosomal proteins <jats:italic>Rpl5a<\/jats:italic>, <jats:italic>Rpl11<\/jats:italic>, and <jats:italic>Rps3a<\/jats:italic>, the <jats:italic>Tcof<\/jats:italic> homolog <jats:italic>Nolc1<\/jats:italic>, or <jats:italic>mdm2<\/jats:italic> separately caused modest craniofacial malformations, whereas these blocking morpholinos synergized with low-dose alcohol to reduce and even eliminate facial elements. Similar results were obtained using a small molecule inhibitor of RNA Polymerase 1, CX5461, whereas p53-blocking morpholinos normalized craniofacial outcomes under high-dose alcohol. Transcriptome analysis affirmed that alcohol suppressed the expression of &gt;150 genes essential for ribosome biogenesis. We conclude that alcohol causes the apoptosis of CNCs, at least in part, by suppressing ribosome biogenesis and invoking a nucleolar stress that initiates their p53-MDM2 mediated apoptosis. We further note that the facial deficits that typify PAE and some ribosomopathies share features including reduced philtrum, upper lip, and epicanthal distance, suggesting the facial deficits of PAE represent, in part, a ribosomopathy.<\/jats:p>","DOI":"10.1371\/journal.pone.0304557","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T18:36:50Z","timestamp":1719599810000},"page":"e0304557","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Alcohol exposure suppresses ribosome biogenesis and causes nucleolar stress in cranial neural crest cells"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7009-653X","authenticated-orcid":true,"given":"George R.","family":"Flentke","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas E.","family":"Wilkie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josh","family":"Baulch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanping","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4782-6857","authenticated-orcid":true,"given":"Susan M.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"issue":"9","key":"pone.0304557.ref001","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1242\/dmm.020529","article-title":"Ribosomopathies: how a common root can cause a tree of pathologies.","volume":"8","author":"N Danilova","year":"2015","journal-title":"Disease Mod Mech"},{"issue":"9","key":"pone.0304557.ref002","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/j.febslet.2014.03.024","article-title":"Diverse diseases from a ubiquitous process: the ribosomopathy paradox","volume":"588","author":"J Armistead","year":"2014","journal-title":"FEBS Lett"},{"issue":"2","key":"pone.0304557.ref003","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1053\/j.seminhematol.2011.02.005","article-title":"Diamond Blackfan Anemia: ribosomal proteins going rogue","volume":"48","author":"SR Ellis","year":"2011","journal-title":"Sem Hematol"},{"issue":"2","key":"pone.0304557.ref004","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1053\/j.seminhematol.2011.01.002","article-title":"Non\u2013Diamond Blackfan Anemia disorders of ribosome function: Shwachman Diamond Syndrome and 5q- Syndrome.","volume":"48","author":"N Burwick","year":"2011","journal-title":"Sem Hematol."},{"issue":"1","key":"pone.0304557.ref005","doi-asserted-by":"crossref","first-page":"e1025185","DOI":"10.1080\/21675511.2015.1025185","article-title":"Ribosomopathies: global process, tissue specific defects.","volume":"3","author":"PC Yelick","year":"2015","journal-title":"Rare Dis"},{"issue":"5","key":"pone.0304557.ref006","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.ajhg.2015.03.011","article-title":"Acrofacial Dysostosis, Cincinnati type, a mandubulofacial dysostosis syndrome with limb anomolies, is caused by POLR1A dysfunction.","volume":"96","author":"KN Weaver","year":"2015","journal-title":"Amer J Hum Gen"},{"key":"pone.0304557.ref007","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1101\/sqb.2001.66.567","article-title":"Economics of ribosome biosynthesis","volume":"66","author":"JR Warner","year":"2001","journal-title":"Cold Spr Harb Symp Quant Biol"},{"key":"pone.0304557.ref008","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1101\/sqb.2001.66.555","article-title":"Ribosomal RNA genes, RNA polymerases, nucleolar structures, and synthesis of rRNA in the yeast Saccharomyces cerevisiae","volume":"66","author":"M. 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