Mutations in the bone morphogenetic protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations

dc.contributor.authorKlem, John R.
dc.contributor.authorSchwantes-An, Tae-Hwi
dc.contributor.authorAbreu, Marco
dc.contributor.authorSuttie, Michael
dc.contributor.authorGray, Raèden
dc.contributor.authorVo, Hieu D. L.
dc.contributor.authorConley, Grace
dc.contributor.authorForoud, Tatiana M.
dc.contributor.authorWetherill, Leah
dc.contributor.authorCollaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)
dc.contributor.authorLovely, C. Ben
dc.contributor.departmentMedical and Molecular Genetics, School of Medicine
dc.date.accessioned2025-05-15T10:43:26Z
dc.date.available2025-05-15T10:43:26Z
dc.date.issued2025
dc.description.abstractFetal alcohol spectrum disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Signaling via bone morphogenetic protein (Bmp) is a key regulatory step of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish carrying mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating that ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. By integrating FASD patient data, we provide the first evidence that variants of the human Bmp receptor gene BMPR1B associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp-ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.
dc.eprint.versionFinal published version
dc.identifier.citationKlem JR, Schwantes-An TH, Abreu M, et al. Mutations in the bone morphogenetic protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations. Dis Model Mech. 2025;18(4):dmm052223. doi:10.1242/dmm.052223
dc.identifier.urihttps://hdl.handle.net/1805/48151
dc.language.isoen_US
dc.publisherThe Company of Biologists
dc.relation.isversionof10.1242/dmm.052223
dc.relation.journalDisease Models & Mechanisms
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectFetal alcohol spectrum disorders
dc.subjectZebrafish
dc.subjectAlcohol
dc.subjectGenetics
dc.subjectEndoderm
dc.subjectJaw development
dc.titleMutations in the bone morphogenetic protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations
dc.typeArticle
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