A Requirement for Zic2 in the Regulation of Nodal Expression Underlies the Establishment of Left-Sided Identity.
A Requirement for Zic2 in the Regulation of Nodal Expression Underlies the Establishment of Left-Sided Identity.
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DOI：
10.1038/s41598-018-28714-1
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发表时间：
2018-07-11
影响因子：
4.6
通讯作者：
Bhattacharya S
中科院分区：
文献类型：
--
作者：
Dykes IM;Szumska D;Kuncheria L;Puliyadi R;Chen CM;Papanayotou C;Lockstone H;Dubourg C;David V;Schneider JE;Keane TM;Adams DJ;Brown SDM;Mercier S;Odent S;Collignon J;Bhattacharya S
已知ZIC2突变会导致前脑无裂畸形（HPE）。ZIC2 HPE先证者的一个子集具有提示偏侧性缺陷的心血管和内脏异常。新型小鼠Zic2突变体的3D成像除了HPE之外还揭示了肺、心脏、脉管系统和内脏中的偏侧性缺陷。对右异构的强烈偏见表明未能建立左身份的侧板中胚层（LPM），表型，不能简单地解释由缺陷的纤毛发生先前指出的Zic2突变体。基因表达分析表明，左决定NODAL依赖的信号级联未能在LPM中激活，并且通常触发该事件的节点处的Nodal的表达本身在这些胚胎中是有缺陷的。对ChiP-seq数据、体外转录测定和诱变的分析揭示了需要低亲和力ZIC 2结合位点来激活Nodal增强子HBE，其通常在节点前体细胞中具有活性。这些数据表明，ZIC 2是正确的Nodal在节点上的表达所必需的，并提出了一种模型，其中ZIC 2在不同的水平上起作用以建立LR不对称性，促进诱导左侧身份的信号的产生和使其分布偏向的纤毛的形态发生。
ZIC2 mutation is known to cause holoprosencephaly (HPE). A subset of ZIC2 HPE probands harbour cardiovascular and visceral anomalies suggestive of laterality defects. 3D-imaging of novel mouse Zic2 mutants uncovers, in addition to HPE, laterality defects in lungs, heart, vasculature and viscera. A strong bias towards right isomerism indicates a failure to establish left identity in the lateral plate mesoderm (LPM), a phenotype that cannot be explained simply by the defective ciliogenesis previously noted in Zic2 mutants. Gene expression analysis showed that the left-determining NODAL-dependent signalling cascade fails to be activated in the LPM, and that the expression of Nodal at the node, which normally triggers this event, is itself defective in these embryos. Analysis of ChiP-seq data, in vitro transcriptional assays and mutagenesis reveals a requirement for a low-affinity ZIC2 binding site for the activation of the Nodal enhancer HBE, which is normally active in node precursor cells. These data show that ZIC2 is required for correct Nodal expression at the node and suggest a model in which ZIC2 acts at different levels to establish LR asymmetry, promoting both the production of the signal that induces left side identity and the morphogenesis of the cilia that bias its distribution.
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影响因子：
20.1
作者：
Dykes, Iain M.;van Bueren, Kelly Lammerts;Scambler, Peter J.
通讯作者：
Scambler, Peter J.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
23.9
作者：
Hu, Guang;Wade, Paul A.
通讯作者：
Wade, Paul A.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
3.5
作者：
Bentham J;Michell AC;Lockstone H;Andrew D;Schneider JE;Brown NA;Bhattacharya S
通讯作者：
Bhattacharya S