Functional Verification of Novel ELMO1 Variants by Live Imaging in Zebrafish.
Functional Verification of Novel ELMO1 Variants by Live Imaging in Zebrafish.
复制标题
通过斑马鱼实时成像对新型 ELMO1 变体进行功能验证。
DOI：
10.3389/fcell.2021.723804
复制
发表时间：
2021
影响因子：
5.5
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Xue R;Wang Y;Wang T;Lyu M;Mo G;Fan X;Li J;Yen K;Yu S;Liu Q;Xu J
ELMO 1（Engulfment and Cell Motility 1）是一种通过ELMO 1-DOCK 2-RAC复合物参与调节细胞运动的基因。与DOCK 2（胞质分裂贡献因子2）缺陷相反，其已被报道与免疫缺陷疾病相关，ELMO 1的变体已与自身免疫性疾病如糖尿病和类风湿性关节炎（RA）相关。为了探索ELMO 1在免疫细胞中的功能，并验证ELMO 1新变体在体内的功能，我们建立了斑马鱼elmo 1突变体模型。活体成像显示，与哺乳动物相似，斑马鱼突变体中中性粒细胞和T细胞的运动性在很大程度上减弱。因此，中性粒细胞对损伤或细菌感染的反应在突变体中显著降低。此外，中性粒细胞的流动性降低可以拯救组成型激活的Rac蛋白的表达，这表明斑马鱼elmo 1突变体功能通过保守的机制。有了这个突变体，三种新的人类ELMO 1变体在斑马鱼中性粒细胞中瞬时特异性表达。p.E90K（c.268G>A）和p.D194G（c.581A>G）两种突变体可以有效地恢复elmo 1突变体中中性粒细胞的运动缺陷;然而，p.R354X（c.1060C>T）突变体未能拯救该突变体。基于这些结果，我们确定了斑马鱼elmo 1在细胞运动中起着保守的作用，类似于高等脊椎动物。使用瞬时表达试验，斑马鱼elmo 1突变体可以作为一个有效的模型，在体内的人类变异验证。
ELMO1 (Engulfment and Cell Motility1) is a gene involved in regulating cell motility through the ELMO1-DOCK2-RAC complex. Contrary to DOCK2 (Dedicator of Cytokinesis 2) deficiency, which has been reported to be associated with immunodeficiency diseases, variants of ELMO1 have been associated with autoimmune diseases, such as diabetes and rheumatoid arthritis (RA). To explore the function of ELMO1 in immune cells and to verify the functions of novel ELMO1 variants in vivo, we established a zebrafish elmo1 mutant model. Live imaging revealed that, similar to mammals, the motility of neutrophils and T-cells was largely attenuated in zebrafish mutants. Consequently, the response of neutrophils to injury or bacterial infection was significantly reduced in the mutants. Furthermore, the reduced mobility of neutrophils could be rescued by the expression of constitutively activated Rac proteins, suggesting that zebrafish elmo1 mutant functions via a conserved mechanism. With this mutant, three novel human ELMO1 variants were transiently and specifically expressed in zebrafish neutrophils. Two variants, p.E90K (c.268G>A) and p.D194G (c.581A>G), could efficiently recover the motility defect of neutrophils in the elmo1 mutant; however, the p.R354X (c.1060C>T) variant failed to rescue the mutant. Based on those results, we identified that zebrafish elmo1 plays conserved roles in cell motility, similar to higher vertebrates. Using the transient-expression assay, zebrafish elmo1 mutants could serve as an effective model for human variant verification in vivo.
登录
查看更多内容
早发作感染患者的遗传DOCK2缺乏。
DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
通讯作者：
Notarangelo LD
影响因子：
5.3
作者：
Itoh, RE;Kurokawa, K;Matsuda, M
通讯作者：
Matsuda, M
DOI：
10.1073/pnas.1600511113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Hathaway, Catherine K.;Chang, Albert S.;Kakoki, Masao
通讯作者：
Kakoki, Masao
影响因子：
4
作者：
Dooley, K;Zon, LI
通讯作者：
Zon, LI
影响因子：
5.8
作者：
Gong, Pan;Chen, Shanshan;Wang, Yubang
通讯作者：
Wang, Yubang