Assemblies of JAG1 and JAG2 determine tracheobronchial cell fate in mucosecretory lung disease.
Assemblies of JAG1 and JAG2 determine tracheobronchial cell fate in mucosecretory lung disease.
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JAG1和JAG2的组件确定粘膜分泌性肺部疾病中的气管支气管细胞命运。
DOI：
10.1172/jci.insight.157380
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发表时间：
2022-08-08
期刊：
影响因子：
8
通讯作者：
Cormet-Boyaka, Estelle
中科院分区：
文献类型：
--
作者：
Reynolds, Susan D.;Hill, Cynthia L.;Alsudayri, Alfahdah;Lallier, Scott W.;Wijeratne, Saranga;Tan, Zheng Hong;Chiang, Tendy;Cormet-Boyaka, Estelle
粘液分泌性肺病损害气道上皮功能，以杯状细胞增生和纤毛细胞发育不全为特征。杯状细胞和纤毛细胞类型通过Notch依赖性机制来源于气管支气管干/祖细胞。尽管Notch受体的特定阵列调节细胞命运决定，但配体Jagged 1（JAG 1）和JAG 2的功能尚不清楚。本研究使用经γ-分泌酶复合物（GSC）抑制剂、中和肽/抗体或WNT/β-连环蛋白途径拮抗剂/激动剂处理的人气液界面培养物检查了JAG 1和JAG 2功能。这些实验表明，JAG 1和JAG 2调节气管支气管上皮细胞的命运决定，然而，他们的角色并不坚持简单的必要性和充分性规则。生物化学研究表明，JAG 1和JAG 2进行翻译后修饰，导致JAG 1 C-末端肽的产生，并调节细胞表面全长JAG 2的丰度。GSC和糖原合成酶激酶3参与了这些翻译后事件，但WNT激动剂/拮抗剂研究和RNA-Seq表明了WNT独立的机制。总的来说，这些数据表明，翻译后修饰产生不同的装配JAG 1和JAG 2，调节Notch信号强度，并确定气管支气管干/祖细胞的命运。
Mucosecretory lung disease compromises airway epithelial function and is characterized by goblet cell hyperplasia and ciliated cell hypoplasia. Goblet and ciliated cell types are derived from tracheobronchial stem/progenitor cells via a Notch-dependent mechanism. Although specific arrays of Notch receptors regulate cell fate determination, the function of the ligands Jagged1 (JAG1) and JAG2 is unclear. This study examined JAG1 and JAG2 function using human air-liquid-interface cultures that were treated with γ-secretase complex (GSC) inhibitors, neutralizing peptides/antibodies, or WNT/β-catenin pathway antagonists/agonists. These experiments revealed that JAG1 and JAG2 regulated cell fate determination in the tracheobronchial epithelium; however, their roles did not adhere to simple necessity and sufficiency rules. Biochemical studies indicated that JAG1 and JAG2 underwent posttranslational modifications that resulted in generation of a JAG1 C-terminal peptide and regulated the abundance of full-length JAG2 on the cell surface. GSC and glycogen synthase kinase 3 were implicated in these posttranslational events, but WNT agonist/antagonist studies and RNA-Seq indicated a WNT-independent mechanism. Collectively, these data suggest that posttranslational modifications create distinct assemblies of JAG1 and JAG2, which regulate Notch signal strength and determine the fate of tracheobronchial stem/progenitor cells.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
6
作者：
Hayes, Don, Jr.;Kopp, Benjamin T.;Reynolds, Susan D.
通讯作者：
Reynolds, Susan D.
影响因子：
4
作者：
Fortini, Mark E.;Bilder, David
通讯作者：
Bilder, David
影响因子：
4.8
作者：
El-Osta, Mohamad A.;Idkowiak-Baldys, Jola;Hannun, Yusuf A.
通讯作者：
Hannun, Yusuf A.