A complex regulatory network of transcription factors critical for ocular development and disease
A complex regulatory network of transcription factors critical for ocular development and disease
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DOI：
10.1093/hmg/ddr038
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发表时间：
2011-04-15
影响因子：
3.5
通讯作者：
Walter, Michael A.
中科院分区：
文献类型：
--
作者：
Acharya, Moulinath;Huang, LiJia;Walter, Michael A.
PITX2 '同源框'和FOXC 1和FOXC 2 '叉头框'转录因子对于眼睛发育至关重要，并且当突变时引起人类眼部疾病。我们已经确定了这些转录因子和转录调节蛋白PRKC凋亡Wilms' tumor 1 regulator（PAWR）之间的生物化学和遗传联系，我们建议将所有这些蛋白质功能性地连接在一个共同的途径中，该途径与眼睛发育密切相关。我们发现了FOXC 1，PITX 2，FOXC 2和PAWR之间的所有二元物理相互作用。重要的是，PAWR调节PITX2、FOXC 1和FOXC 2激活其遗传靶点的能力。与FOXC 1或FOXC 2一起，PAWR增加PITX2活性。PAWR在不存在FOXC 1或FOXC 2的情况下降低PITX 2活性。同时，PAWR还对不同的FOXC靶位点发挥不同的调控作用。此外，在斑马鱼中，pitx2，foxc1和pawr的吗啉敲低表明PAWR，FOXC 1和PITX2在遗传上相互作用，并且处于相同的发育途径。这些数据首次将PITX2，FOXC 1，FOXC 2和PAWR联系到一个共同的调控途径中。因此，我们已经确定了三个转录因子之间的功能联系，调节PAWR，我们提出的基础相似的眼部表型和青光眼病理引起的这些基因的突变。
The PITX2 'homeobox' and FOXC1 and FOXC2 'forkhead box' transcription factors are critical for eye development and cause human ocular diseases when mutated. We have identified biochemical and genetic links between these transcription factors and a transcriptional regulator protein PRKC apoptosis Wilms' tumor 1 regulator (PAWR) that we propose to functionally connect all these proteins in a common pathway critically involved in eye development. We discovered all binary physical interactions between FOXC1, PITX2, FOXC2 and PAWR. Importantly, PAWR modulates the abilities of PITX2, FOXC1 and FOXC2 to activate their genetic targets. Together with either FOXC1 or FOXC2, PAWR increases PITX2 activity. PAWR reduces PITX2 activity in the absence of FOXC1 or FOXC2. At the same time, PAWR also exerts different regulatory effects on different FOXC target sites. Furthermore, morpholino knockdown of pitx2, foxc1 and pawr in zebrafish indicate that PAWR, FOXC1 and PITX2 genetically interact, and are in the same developmental pathway. These data for the first time tie PITX2, FOXC1, FOXC2 and PAWR into a common regulatory pathway. We have therefore identified a functional link between three transcription factors, modulated by PAWR, which we propose underlies the similar ocular phenotypes and glaucoma pathology caused by mutations of these genes.