Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2.
Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2.
复制标题
DOI：
10.1016/j.ydbio.2010.01.027
复制
发表时间：
2010-04-01
影响因子：
2.7
通讯作者：
Duester, Gregg
中科院分区：
文献类型：
--
作者：
Kumar, Sandeep;Duester, Gregg
眼睛发育过程中的形态发生需要视黄酸（RA）受体加上RA合成酶，RA信号传导的丧失导致与视周间充质中Pitx 2表达丧失相关的眼部疾病。在眼发育期间，几种Wnt信号传导组分在眼组织中表达，包括Dkk 2，其编码Wnt/β-连环蛋白信号传导的抑制剂，先前显示其在视周间充质中由Pitx 2诱导。在这里，我们研究了眼睛发育过程中RA和Wnt信号之间的潜在串扰。使用Raldh 1/Raldh 3双无效小鼠缺乏眼部RA合成的遗传研究表明，Pitx 2和Dkk 2在视周间充质中均下调。染色质免疫沉淀和凝胶迁移率变化的研究表明，存在一个DR 5 RA反应元件上游的Pitx 2结合所有三个RA受体在胚胎眼。Axin 2是Wnt/β-catenin信号的内源性读出器，在RA缺陷胚胎的角膜和视周间充质中上调。此外，Wnt 5a在RA缺陷眼的视周间充质中的表达增加。我们的研究结果表明，过度激活的Wnt信号在视周间充质的RA缺陷小鼠，这可能是负责异常发展，导致有缺陷的视杯，角膜和眼睑形态发生。
Morphogenesis during eye development requires retinoic acid (RA) receptors plus RA-synthesizing enzymes, and loss of RA signaling leads to ocular disorders associated with loss of Pitx2 expression in perioptic mesenchyme. Several Wnt signaling components are expressed in ocular tissues during eye development including Dkk2, encoding an inhibitor of Wnt/β-catenin signaling, which was previously shown to be induced by Pitx2 in the perioptic mesenchyme. Here, we investigated potential cross-talk between RA and Wnt signaling during ocular development. Genetic studies using Raldh1/Raldh3 double null mice deficient for ocular RA synthesis demonstrated that Pitx2 and Dkk2 were both down-regulated in perioptic mesenchyme. Chromatin immunoprecipitation and gel mobility shift studies demonstrated the existence of a DR5 RA response element upstream of Pitx2 that binds all three RA receptors in embryonic eye. Axin2, an endogenous readout of Wnt/β-catenin signaling, was up-regulated in cornea and perioptic mesenchyme of RA deficient embryos. Also, expression of Wnt5a was expanded in perioptic mesenchyme of RA deficient eyes. Our findings demonstrate excessive activation of Wnt signaling in the perioptic mesenchyme of RA deficient mice which may be responsible for abnormal development leading to defective optic cup, cornea, and eyelid morphogenesis.
登录
查看更多内容
影响因子：
64.5
作者：
Duester G
通讯作者：
Duester G
DOI：
10.1016/j.jsbmb.2005.05.005
发表时间：
2005-09-01
影响因子：
4.1
作者：
Balmer, JE;Blomhoff, R
通讯作者：
Blomhoff, R
影响因子：
2.7
作者：
Matt, Nicolas;Ghyselinck, Norbert B.;Dupe, Valerie
通讯作者：
Dupe, Valerie
与维甲酸诱导胚胎癌细胞分化有关的全基因表达谱
影响因子：
2.5
作者：
Eifert, Cheryl;Sangster-Guity, Niquiche;McCormick, Paulette J.
通讯作者：
McCormick, Paulette J.
影响因子：
14.9
作者：
DIGNAM, JD;LEBOVITZ, RM;ROEDER, RG
通讯作者：
ROEDER, RG