Ethanol-induced Lower Jaw Loss in Bmp Signaling Pathway Mutants

Bmp 信号通路突变体中乙醇诱导的下颌缺失

• 批准号: 8551363
• 负责人: Charles Benjamin Lovely
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-07 至 2015-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551363
• 关键词: Affect; Alcohol consumption; Anterior; Candidate Disease Gene; Cephalic; Child; Complex; Data; Defect; Development; Diagnosis; Dysmorphology; Embryo; Endoderm; Epithelial; Ethanol; Etiology; Fetal Alcohol Spectrum Disorder; Gene Targeting; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Goals; Human; Image Analysis; In Situ; Jaw; Label; Lead; Life; Light; Maps; Meckel' s cartilage; Modeling; Morphogenesis; Mutation; Neural Crest; Neural Crest Cell; Pathway interactions; Patients; Pattern; Perinatal Exposure; Phenotype; Physical condensation; Population; Signal Pathway; Signal Transduction; Skeleton; Source; Sphingosine; Testing; Time; Tissues; Transgenic Organisms; Translating; Transplantation; United States; Variant; Work; Zebrafish; alcohol exposure; alcohol sensitivity; bone morphogenic protein; cartilage development; cell behavior; craniofacial; dosage; gene function; insight; member; mutant; oral ectoderm; receptor; research study

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder (FASD) describes a wide array of ethanol-induced developmental defects, including craniofacial dysmorphology, such as lower jaw hypoplasia. It affects approximately 1 in 100 children born in the United States each year. Although fetal exposure to alcohol causes FASD, virtually nothing of the genetics behind these ethanol-induced craniofacial defects is understood. The majority of the craniofacial skeleton, including the lower jaw, is generated by cranial neural crest cells. Complex interactions between neural crest cells and epithelial tissues are important for craniofacial morphogenesis. These interactions are orchestrated by, among others, the Bone Morphogenic Protein (Bmp) signaling pathway. Preliminary data using zebrafish demonstrate that members of the Bmp signaling pathway are ethanol-sensitive loci. While bmp2b homozygous mutant embryos die before craniofacial development initiates, bmp2b heterozygous embryos and bmp4 homozygous mutant embryos (together termed Bmp-pathway mutants) undergo normal craniofacial development. However, Bmp-pathway mutants display ethanol-induced defects to Meckel's cartilage the lower jaw. Mutation of the sphingosine receptor, s1pr2, causes strikingly similar defects to Meckel's cartilage due to disrupted morphogenesis of the anterior endoderm and subsequent defects to the oral ectoderm. The findings suggest the hypothesis that ethanol disrupts anterior endoderm morphogenesis in Bmp-pathway mutants resulting in defects in the oral ectoderm and subsequent craniofacial development. In Specific Aim 1 of this proposal, 1) how ethanol perturbs cell behaviors during endodermal morphogenesis in Bmp-pathway mutants will be visualized and 2) the interaction between the endoderm and oral ectoderm will be directly visualized through generation of a double transgenic line that labels the endoderm and the oral ectoderm. In Specific Aim 2, the mechanism of Bmp-pathway signaling in patterning the lower jaw will be determined through transplantation experiments and in situ marker analyses. In Specific Aim 3, an ethanol- sensitive mutant recovered from a forward genetic screen will be mapped and the overall ethanol sensitivity characterized. Overall, this application will provide greater insight into the gene-ethanol interactions that lead to the variability of craniofacial defects in FASD. In addition, because of the conservation of gene function between zebrafish and humans, this work will directly translate to studies of candidate genes in human populations and allow better for diagnosis and treatment of FASD.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）描述了一系列广泛的乙醇诱导的发育缺陷，包括颅面畸形，如下颌发育不全。在美国，每年每100个出生的孩子中就有1个患有这种疾病。虽然胎儿暴露于酒精中会导致FASD，但实际上，这些酒精诱发的颅面缺陷背后的遗传学还不清楚。颅面骨骼的大部分，包括下颚，都是由颅神经嵴细胞产生的。神经嵴细胞和上皮组织之间复杂的相互作用对颅面形态发生至关重要。这些相互作用是由骨形态发生蛋白（Bmp）信号通路协调的。斑马鱼的初步数据表明Bmp信号通路的成员是乙醇敏感位点。虽然bmp2b纯合突变胚胎在颅面发育开始前死亡，但bmp2b杂合胚胎和bmp4纯合突变胚胎（统称为bmp通路突变体）可以正常颅面发育。然而，bmp通路突变体显示乙醇诱导的下颌梅克尔软骨缺陷。鞘氨醇受体s1pr2的突变导致与梅克尔软骨惊人相似的缺陷，原因是前内胚层的形态发生被破坏，口腔外胚层随后出现缺陷。研究结果表明，乙醇破坏bmp通路突变体的前内胚层形态发生，导致口腔外胚层缺陷和随后的颅面发育。在本提案的Specific Aim 1中，1)将可视化乙醇如何干扰bmp通路突变体内胚层形态发生过程中的细胞行为；2)将通过生成标记内胚层和口腔外胚层的双转基因系直接可视化内胚层和口腔外胚层之间的相互作用。在Specific Aim 2中，我们将通过移植实验和原位标记分析来确定bmp通路信号在下颌定形中的作用机制。在特异性目标3中，从正向遗传筛选中恢复的乙醇敏感突变体将被绘制，并对总体乙醇敏感性进行表征。总的来说，这一应用将提供更深入的了解基因-乙醇相互作用，导致FASD颅面缺陷的可变性。此外，由于斑马鱼和人类之间基因功能的保守性，这项工作将直接转化为人类群体中候选基因的研究，从而更好地诊断和治疗FASD。