Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis
Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis
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DOI：
10.1093/hmg/ddl008
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发表时间：
2006-03-15
影响因子：
3.5
通讯作者：
Walter, MA
中科院分区：
文献类型：
--
作者：
Berry, FB;Lines, MA;Walter, MA
Axenoblast-Rieger眼发育不全与人类PITX 2和FOXC 1基因突变有关，这两种基因分别编码同源结构域和叉头型转录因子。我们已经确定了FOXC 1和PITX 2之间的功能联系，我们建议支持这些基因突变引起的类似Axenetri-Rieger表型。FOXC 1和PITX 2A在物理上相互作用，这种相互作用需要两种蛋白质上的关键功能结构域：FOXC 1的C末端激活结构域和PITX 2的同源结构域。免疫荧光进一步显示PITX 2A和FOXC 1共定位在一个共同的核亚区室。此外，PITX 2A可以作为FOXC 1反式活性的负调节剂。这项工作将两种蛋白质联系到一个共同的途径，并解释了为什么增加FOXC 1基因剂量会产生类似于PITX 2缺失和突变的表型。尽管通过FOXC 1或PITX 2突变导致FOXC 1靶基因表达失调，但仍会出现眼部表型。最终，PITX 2功能缺失突变具有复合效应：PITX 2靶基因的表达减少，加上FOXC 1调节靶点的广泛激活。我们的研究结果表明，FOXC 1和PITX 2A之间的功能相互作用的基础上的敏感性，FOXC 1基因剂量在Axenovirus-Rieger综合征和相关的眼前节发育不良。
Axenfeld-Rieger ocular dysgenesis is associated with mutations of the human PITX2 and FOXC1 genes, which encode transcription factors of the homeodomain and forkhead types, respectively. We have identified a functional link between FOXC1 and PITX2 which we propose underpins the similar Axenfeld-Rieger phenotype caused by mutations of these genes. FOXC1 and PITX2A physically interact, and this interaction requires crucial functional domains on both proteins: the C-terminal activation domain of FOXC1 and the homeodomain of PITX2. Immunofluorescence further shows PITX2A and FOXC1 to be colocalized within a common nuclear subcompartment. Furthermore, PITX2A can function as a negative regulator of FOXC1 transactivity. This work ties both proteins into a common pathway and offers an explanation of why increased FOXC1 gene dosage produces a phenotype resembling that of PITX2 deletions and mutations. Ocular phenotypes arise despite the deregulated expression of FOXC1-target genes through mutations in FOXC1 or PITX2. Ultimately, PITX2 loss of function mutations have a compound effect: the reduced expression of PITX2-target genes coupled with the extensive activation of FOXC1-regulated targets. Our findings indicate that the functional interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and related anterior segment dysgeneses.