The ribosome biogenesis protein Esf1 is essential for pharyngeal cartilage formation in zebrafish
The ribosome biogenesis protein Esf1 is essential for pharyngeal cartilage formation in zebrafish
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核糖体生物发生蛋白 Esf1 对于斑马鱼咽软骨的形成至关重要
DOI：
10.1111/febs.14622
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发表时间：
2018-09-01
期刊：
影响因子：
5.4
通讯作者：
Li, Yun
中科院分区：
文献类型：
--
作者：
Chen, Jian-Yang;Tan, Xungang;Li, Yun
颅面畸形是常见的先天性出生缺陷，通常是由颅神经嵴细胞发育异常引起的。一些核仁核糖体生物发生因子涉及神经嵴疾病，也称为神经损伤。然而，核糖体生物发生和神经嵴细胞（NCC）发育的潜在机制仍有待阐明。在这里，我们报告了一种具有CRISPR/Cas9生成的esf 1突变的新型斑马鱼模型，该模型表现出严重的NCC衍生的咽软骨损失以及眼睛，大脑和心脏的缺陷。几个典型的NCC标记，包括sox 10，dlx 2a，nrp 2b，crestin，vgll 2a和sox 9a，在esf 1突变体的头部表达减少，这表明esf 1在斑马鱼NCC的发育中起作用。我们证明，与酵母相似，斑马鱼esf 1的缺失导致18 S rRNA生物合成和核糖体生物合成的缺陷。我们还发现突变体中p53信号传导以及凋亡的强烈上调和不良增殖。p53失活挽救了在esf 1突变体中观察到的早期组织缺损和咽软骨缺损，表明在esf 1突变体中观察到的细胞死亡和咽软骨缺损增加是通过上调p53信号通路介导的。基于移植分析，我们发现esf 1在NCC中以细胞自主的方式发挥功能。总之，我们的研究结果表明，esf 1是需要NCC的发展和咽软骨形成。这些研究为研究核糖体生物合成缺陷与颅面神经损伤之间的关系提供了一个潜在的模型。
Craniofacial malformations are common congenital birth defects and usually caused by abnormal development of the cranial neural crest cells. Some nucleolar ribosome biogenesis factors are implicated in neural crest disorders also known as neurocristopathies. However, the underlying mechanisms linking ribosome biogenesis and neural crest cell (NCC) development remain to be elucidated. Here we report a novel zebrafish model with a CRISPR/Cas9‐generated esf1 mutation, which exhibits severe NCC‐derived pharyngeal cartilage loss and defects in the eyes, brain, and heart. The expression of several typical NCC markers, including sox10, dlx2a, nrp2b, crestin, vgll2a, and sox9a, was reduced in the head of the esf1 mutants, which indicates that esf1 plays a role in the development of zebrafish NCCs. We demonstrate that, similar to the yeast, loss of esf1 in zebrafish leads to defects in 18S rRNA biogenesis and ribosome biogenesis. We also show strong upregulation of p53 signaling as well as apoptosis, and poor proliferation in mutants. Inactivation of p53 rescues the early tissue defects and pharyngeal cartilage loss observed in esf1 mutants, indicating that increased cell death and pharyngeal cartilage defects observed in esf1 mutants are mediated via upregulated p53 signaling pathways. Based on transplantation analysis, we found esf1 functions in NCC in a cell autonomous fashion. Together, our results suggest that esf1 is required for NCC development and pharyngeal cartilage formation. These studies provide a potential model for investigating the relationship between ribosome biogenesis defects and craniofacial neurocristopathies.