Functions of huntingtin in germ layer specification and organogenesis.
Functions of huntingtin in germ layer specification and organogenesis.
复制标题
亨廷汀在细菌层规格和器官发生中的功能。
DOI：
10.1371/journal.pone.0072698
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mehler MF
中科院分区：
文献类型：
--
作者：
Nguyen GD;Molero AE;Gokhan S;Mehler MF
Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC) expansion, differentiation and induction experiments using huntingtin knock-out (KO) and mutant huntingtin knock-in (Q111) mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities.
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影响因子：
3.7
作者：
Abrajano JJ;Qureshi IA;Gokhan S;Zheng D;Bergman A;Mehler MF
通讯作者：
Mehler MF
DOI：
10.1159/000339528
发表时间：
2013
期刊：
Neuro-degenerative diseases
影响因子：
--
作者：
Dogan I;Eickhoff SB;Schulz JB;Shah NJ;Laird AR;Fox PT;Reetz K
通讯作者：
Reetz K
诱导多能干细胞作为加速患者和疾病特异性药物发现的模型。
影响因子：
4.1
作者：
Gunaseeli I;Doss MX;Antzelevitch C;Hescheler J;Sachinidis A
通讯作者：
Sachinidis A
影响因子：
6.1
作者：
Castiglioni, Valentina;Onorati, Marco;Cattaneo, Elena
通讯作者：
Cattaneo, Elena
影响因子：
3.5
作者：
Hamazaki, T;Iiboshi, Y;Terada, N
通讯作者：
Terada, N