amer1 Regulates Zebrafish Craniofacial Development by Interacting with the Wnt/β-Catenin Pathway.
amer1 Regulates Zebrafish Craniofacial Development by Interacting with the Wnt/β-Catenin Pathway.
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amer1通过与Wnt/β-Catenin通路相互作用调控斑马鱼颅面发育。
DOI：
10.3390/ijms25020734
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发表时间：
2024-01-05
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
先天性小耳畸形是一种罕见的先天性颅面畸形，会对患者的外观和听力造成严重损害。与小耳畸形闭锁相关的遗传因素尚未确定。在两个双胞胎家族中，AMER 1基因已被鉴定为小耳畸形闭锁的潜在致病基因。使用CRISPR/Cas9构建amer 1嵌合体敲低斑马鱼模型。研究了敲除斑马鱼颅神经嵴细胞的表型和发育过程。通过qPCR、蛋白质印迹和免疫荧光测定来检查Wnt/β-连环蛋白途径的组分。应用Wnt/β-catenin通路的可逆抑制剂IWR-1-endo来挽救异常表型。目前的研究表明，斑马鱼下颌软骨的发育受到使用CRISPR/Cas9敲除amer 1的严重影响。具体而言，amer 1敲低被发现影响颅神经嵴细胞的增殖和凋亡，以及它们向软骨细胞的分化。在机制上，amer 1对Wnt/β-catenin通路产生拮抗作用。IWR-1-endo的应用可部分挽救异常表型。我们证明amer 1通过与Wnt/β-catenin通路相互作用对斑马鱼颅面发育至关重要。这些发现为研究amer 1在斑马鱼下颌骨发育中的作用以及人类amer 1基因突变引起的小耳畸形-闭锁的病理学提供了重要的见解。
Microtia-atresia is a rare type of congenital craniofacial malformation causing severe damage to the appearance and hearing ability of affected individuals. The genetic factors associated with microtia-atresia have not yet been determined. The AMER1 gene has been identified as potentially pathogenic for microtia-atresia in two twin families. An amer1 mosaic knockdown zebrafish model was constructed using CRISPR/Cas9. The phenotype and the development process of cranial neural crest cells of the knockdown zebrafish were examined. Components of the Wnt/β-catenin pathway were examined by qPCR, Western blotting, and immunofluorescence assay. IWR-1-endo, a reversible inhibitor of the Wnt/β-catenin pathway, was applied to rescue the abnormal phenotype. The present study showed that the development of mandibular cartilage in zebrafish was severely compromised by amer1 knockdown using CRISPR/Cas9. Specifically, amer1 knockdown was found to affect the proliferation and apoptosis of cranial neural crest cells, as well as their differentiation to chondrocytes. Mechanistically, amer1 exerted an antagonistic effect on the Wnt/β-catenin pathway. The application of IWR-1-endo could partially rescue the abnormal phenotype. We demonstrated that amer1 was essential for the craniofacial development of zebrafish by interacting with the Wnt/β-catenin pathway. These findings provide important insight into the role of amer1 in zebrafish mandibular development and the pathology of microtia-atresia caused by AMER1 gene mutations in humans.
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影响因子：
5.5
作者：
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通讯作者：
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0.4
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Kukreja, Shyam
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4.8
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通讯作者：
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