Klem John R, Schwantes-An Tae-Hwi, Abreu Marco, Suttie Michael, Gray Raeden, Vo Hieu, Conley Grace, Foroud Tatiana M, Wetherill Leah, Lovely C Ben
bioRxiv. 2024 Oct 24:2023.06.28.546932. doi: 10.1101/2023.06.28.546932.
Fetal 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. Bmp signaling is a key regulator of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. Integrating FASD patient data, we provide the first evidence that variants in the human Bmp receptor gene 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.
In this study, we apply a unique combination of zebrafish-based approaches and human genetic and facial dysmorphology analyses to resolve the cellular mechanisms driven by the ethanol-sensitive Bmp pathway.
胎儿酒精谱系障碍（FASD）描述了乙醇诱导的发育缺陷，包括颅面畸形。虽然乙醇敏感基因突变会导致面部畸形，但其影响的细胞机制仍不清楚。骨形态发生蛋白（Bmp）信号是驱动面部发育的上皮形态发生的关键调节因子，提供了一种可能的乙醇敏感机制。我们发现，Bmp信号成分的斑马鱼突变体对乙醇敏感，并影响前咽内胚层的形状和基因表达，表明乙醇诱导的前咽内胚层畸形会导致面部畸形。整合FASD患者数据，我们提供了首个证据，证明人类Bmp受体基因的变异与颌骨体积的乙醇相关差异有关。我们的结果表明，乙醇暴露会破坏面部上皮细胞的正常形态发生以及组织间相互作用，这些变化反映了整体内脏颅骨形状的改变，并可预测人类颌骨发育中Bmp与乙醇的关联。我们的数据提供了一个机制范例，将乙醇与FASD面部缺陷背后的上皮细胞行为破坏联系起来。
在本研究中，我们应用了基于斑马鱼的方法与人类遗传学和面部畸形分析的独特组合，以解析由乙醇敏感的Bmp通路驱动的细胞机制。
