Mice doubly deficient in Six4 and Six5 show ventral body wall defects reproducing human omphalocele.
Mice doubly deficient in Six4 and Six5 show ventral body wall defects reproducing human omphalocele.
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DOI：
10.1242/dmm.034611
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发表时间：
2018-10-25
影响因子：
4.3
通讯作者：
Kawakami K
中科院分区：
文献类型：
--
作者：
Takahashi M;Tamura M;Sato S;Kawakami K
脐膨出是一种人体先天性腹侧腹壁闭合异常，可能是由原发性腹壁（PAW）形成受损和/或腹肌发育缺陷引起的。在这里，我们报告说，小鼠的同源异型盒基因Six 4和Six 5的双重缺陷表现出相同的腹体壁闭合缺陷，在人类脐膨出。SIX 4和SIX 5定位于PAW的表面外胚层细胞和体细胞中胚层来源的间充质和体腔上皮细胞（CEC）。Six4−/−; 6只5 −/−胎仔表现出大脐膨出伴肝脏和肠突出，或小脐膨出伴肠突出，完全昏迷。在E11.5阶段，在成肌细胞迁移到PAW之前，Six 4 −/−; Six 5 −/−胚胎的脐环向前移动，其横向尺寸大于正常胚胎。在E10.5时，Six 4 −/−; Six 5 −/−胚胎中左右PAW中的表面外胚层细胞和右PAW中的体细胞中胚层衍生细胞的增殖率低于野生型胚胎。在E11.25的Six 4 −/−; Six 5 −/−胚胎中，PAW的CEC向圆形间皮祖细胞的过渡受损，PAW的内体腔表面相对光滑。此外，Six 4在PAW CEC中的过表达促进了CEC的侵入。综上所述，我们的研究结果表明Six 4和Six 5是PAW生长和形态变化所必需的，这些过程的损伤与脐环的异常定位和扩张有关，从而导致脐膨出。总结：同源异型盒基因Six 4和Six 5参与调节初级体壁中的细胞增殖和间皮形成，Six 4 −/−; Six 5 −/−小鼠是人类中间型脐膨出的合适动物模型。
Omphalocele is a human congenital anomaly in ventral body wall closure and may be caused by impaired formation of the primary abdominal wall (PAW) and/or defects in abdominal muscle development. Here, we report that mice doubly deficient in homeobox genes Six4 and Six5 showed the same ventral body wall closure defects as those seen in human omphalocele. SIX4 and SIX5 were localized in surface ectodermal cells and somatic mesoderm-derived mesenchymal and coelomic epithelial cells (CECs) in the PAW. Six4−/−;Six5−/− fetuses exhibited a large omphalocele with protrusion of both the liver and intestine, or a small omphalocele with protrusion of the intestine, with complete penetrance. The umbilical ring of Six4−/−;Six5−/− embryos was shifted anteriorly and its lateral size was larger than that of normal embryos at the E11.5 stage, before the onset of myoblast migration into the PAW. The proliferation rates of surface ectodermal cells in the left and right PAW and somatic mesoderm-derived cells in the right PAW were lower in Six4−/−;Six5−/− embryos than those of wild-type embryos at E10.5. The transition from CECs of the PAW to rounded mesothelial progenitor cells was impaired and the inner coelomic surface of the PAW was relatively smooth in Six4−/−;Six5−/− embryos at E11.25. Furthermore, Six4 overexpression in CECs of the PAW promoted ingression of CECs. Taken together, our results suggest that Six4 and Six5 are required for growth and morphological change of the PAW, and the impairment of these processes is linked to the abnormal positioning and expansion of the umbilical ring, which results in omphalocele. Summary: The homeobox genes Six4 and Six5 are involved in the regulation of cell proliferation and mesothelium formation in the primary body wall, and Six4−/−;Six5−/− mice are a suitable animal model for human middle-type omphalocele.
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DOI：
10.1084/jem.194.1.13
发表时间：
2001-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Doyonnas R;Kershaw DB;Duhme C;Merkens H;Chelliah S;Graf T;McNagny KM
通讯作者：
McNagny KM
影响因子：
4.8
作者：
Hayashida, Yasushi;Urata, Yoshishige;Ihara, Yoshito
通讯作者：
Ihara, Yoshito
影响因子：
64.8
作者：
Dickinson ME;Flenniken AM;Ji X;Teboul L;Wong MD;White JK;Meehan TF;Weninger WJ;Westerberg H;Adissu H;Baker CN;Bower L;Brown JM;Caddle LB;Chiani F;Clary D;Cleak J;Daly MJ;Denegre JM;Doe B;Dolan ME;Edie SM;Fuchs H;Gailus-Durner V;Galli A;Gambadoro A;Gallegos J;Guo S;Horner NR;Hsu CW;Johnson SJ;Kalaga S;Keith LC;Lanoue L;Lawson TN;Lek M;Mark M;Marschall S;Mason J;McElwee ML;Newbigging S;Nutter LM;Peterson KA;Ramirez-Solis R;Rowland DJ;Ryder E;Samocha KE;Seavitt JR;Selloum M;Szoke-Kovacs Z;Tamura M;Trainor AG;Tudose I;Wakana S;Warren J;Wendling O;West DB;Wong L;Yoshiki A;International Mouse Phenotyping Consortium;Jackson Laboratory;Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS);Charles River Laboratories;MRC Harwell;Toronto Centre for Phenogenomics;Wellcome Trust Sanger Institute;RIKEN BioResource Center;MacArthur DG;Tocchini-Valentini GP;Gao X;Flicek P;Bradley A;Skarnes WC;Justice MJ;Parkinson HE;Moore M;Wells S;Braun RE;Svenson KL;de Angelis MH;Herault Y;Mohun T;Mallon AM;Henkelman RM;Brown SD;Adams DJ;Lloyd KC;McKerlie C;Beaudet AL;Bućan M;Murray SA
通讯作者：
Murray SA
DOI：
10.1523/jneurosci.0894-12.2012
发表时间：
2012-05-30
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lian G;Lu J;Hu J;Zhang J;Cross SH;Ferland RJ;Sheen VL
通讯作者：
Sheen VL
影响因子：
2.7
作者：
Brewer, S;Williams, T
通讯作者：
Williams, T