骨形态发生蛋白信号通路的突变使斑马鱼和人类对乙醇诱导的颌骨畸形敏感。

John R Klem, Tae-Hwi Schwantes-An, Marco Abreu, Michael Suttie, Raeden Gray, Hieu Vo, Grace Conley, Tatiana M Foroud, Leah Wetherill, C Ben Lovely
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引用次数: 0

摘要

背景:胎儿酒精谱系障碍(FASD)描述了一系列乙醇诱导的发育缺陷,包括常见的颅面畸形。虽然乙醇敏感的基因突变是导致面部畸形的主要原因,但这些面部畸形背后受影响的细胞机制仍然未知。骨形态发生蛋白(Bmp)信号通路是上皮形态发生驱动面部发育的关键调节因子,为面部骨骼畸形提供了一种可能的乙醇敏感机制。方法:使用斑马鱼,我们测试了乙醇诱导的面部畸形的Bmp途径成分的几种突变体。从受精(hpf)后10-18小时,将突变胚胎暴露于培养基中的乙醇中。暴露的斑马鱼在36hpf固定以通过免疫荧光分析咽前内胚层的大小和形状,或者在受精后5天(dpf)固定以用阿尔西安蓝/茜素红染色定量检查面部骨骼的形状。结合人类遗传数据,我们筛选了接触乙醇的儿童下颌体积中Bmp与乙醇的相关性。结果:我们发现Bmp途径的突变使斑马鱼胚胎对乙醇诱导的咽前内胚层形状畸形敏感,导致口腔外胚层中fgf8a的表达改变。这些变化与内脏颅骨的形状变化相关,表明乙醇诱导的咽前内胚层畸形会导致面部畸形。Bmp受体基因BMPR1B的变异与人类下颌体积的乙醇相关差异有关。结论:我们首次表明,乙醇暴露会破坏面部上皮细胞的正常形态发生和组织之间的相互作用。在斑马鱼早期发育过程中,咽前内胚层-口腔外胚层信号轴的这些形状变化反映了在内脏颅骨中观察到的总体形状变化,并预测了人类颌骨发育中Bmp-乙醇的相关性。总之,我们的工作提供了一个机制范式,将乙醇的影响与FASD面部缺陷的上皮细胞行为联系起来。
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Mutations in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations.

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 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.

Summary statement: 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.

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