Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity.
Nicotinic acetylcholine receptor signaling maintains epithelial barrier integrity.
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DOI：
10.7554/elife.86381
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发表时间：
2023-12-08
期刊：
影响因子：
7.7
通讯作者：
Jasper H
中科院分区：
文献类型：
--
作者：
Katheder NS;Browder KC;Chang D;De Maziere A;Kujala P;van Dijk S;Klumperman J;Lu TC;Li H;Lai Z;Sangaraju D;Jasper H
上皮屏障的破坏是气道、肺和肠道慢性退行性疾病的常见疾病表现。广泛的人类遗传研究已经确定了这些疾病的风险位点，包括慢性阻塞性肺疾病（COPD）和炎症性肠病。与这些基因座相关的基因尚未完全确定，这些基因的功能表征需要在模式生物中进行广泛的研究。在这里，我们报告了在黑腹果蝇中进行筛选的结果，该筛选允许基于人类全基因组关联研究（GWAS）中鉴定的风险位点选择COPD风险基因的快速识别、验证和优先排序。利用果蝇肠道屏障功能障碍作为读数，我们的研究结果验证了候选基因扰动对56%的病例上皮屏障功能的影响，从而得出了一个优先的靶基因列表。我们进一步报道了这些基因的一个家族在果蝇中的功能特征，编码烟碱乙酰胆碱受体（nAchR）亚基。我们发现蝇肠肠细胞中的nAchR信号通过调节周围营养基质的产生来促进上皮屏障功能和上皮稳态。我们的研究结果确定了copd相关基因对上皮屏障维持至关重要，并为上皮nAchR信号在体内平衡中的作用提供了见解。
Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung, and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in Drosophila melanogaster that allowed for rapid identification, validation, and prioritization of COPD risk genes that were selected based on risk loci identified in human genome-wide association studies (GWAS). Using intestinal barrier dysfunction in flies as a readout, our results validate the impact of candidate gene perturbations on epithelial barrier function in 56% of the cases, resulting in a prioritized target gene list. We further report the functional characterization in flies of one family of these genes, encoding for nicotinic acetylcholine receptor (nAchR) subunits. We find that nAchR signaling in enterocytes of the fly gut promotes epithelial barrier function and epithelial homeostasis by regulating the production of the peritrophic matrix. Our findings identify COPD-associated genes critical for epithelial barrier maintenance, and provide insight into the role of epithelial nAchR signaling for homeostasis.
影响因子：
3.7
作者：
Cui K;Ge X;Ma H
通讯作者：
Ma H
影响因子：
16.6
作者：
Routhier J;Pons S;Freidja ML;Dalstein V;Cutrona J;Jonquet A;Lalun N;Mérol JC;Lathrop M;Stitzel JA;Kervoaze G;Pichavant M;Gosset P;Tournier JM;Birembaut P;Dormoy V;Maskos U
通讯作者：
Maskos U