Aristaless Related Homeobox (ARX) Interacts with β-Catenin, BCL9, and P300 to Regulate Canonical Wnt Signaling.
Aristaless Related Homeobox (ARX) Interacts with β-Catenin, BCL9, and P300 to Regulate Canonical Wnt Signaling.
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与二元相关的同型同源物（ARX）与β-catenin，bcl9和p300相互作用，以调节规范的Wnt信号。
DOI：
10.1371/journal.pone.0170282
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Cho G
中科院分区：
文献类型：
--
作者：
Cho IT;Lim Y;Golden JA;Cho G
Aristaless Related Homeobox(ARX)基因突变与一系列结构性(无脑)和功能性(癫痫和智力障碍)神经发育障碍有关。这种单一转录因子的突变如何导致如此广泛的表型仍然知之甚少。我们假设ARX通过与特定转录因子/辅因子的不同相互作用来调节不同细胞类型中独特的靶基因。为了确定ARX相互作用蛋白，我们进行了无偏倚的蛋白质组学筛选，并在皮质祖细胞中鉴定了WNT/β-连环蛋白信号通路的几个组成部分，包括β-连环蛋白(CTNNB1)、B细胞CLL/淋巴瘤9(BCL9)和富含亮氨酸重复序列的无飞行相互作用蛋白2(LRRFIP2)。我们的数据表明，ARX正向调节WNT/β-连环蛋白信号，ARX的C-末端结构域与β-连环蛋白中的螳螂重复序列相互作用，促进WNT/β-连环蛋白信号转导。此外，我们还发现bcl9和P300还与ARx相互作用，调节Wnt/β-catenin信号转导。这些数据为ARX如何独特地调节皮质神经发生提供了新的见解，并将ARX的功能与Wnt/β-catenin信号联系起来。
Mutations in the Aristaless Related Homeobox (ARX) gene are associated with a spectrum of structural (lissencephaly) and functional (epilepsy and intellectual disabilities) neurodevelopmental disorders. How mutations in this single transcription factor can result in such a broad range of phenotypes remains poorly understood. We hypothesized that ARX functions through distinct interactions with specific transcription factors/cofactors to regulate unique target genes in different cell types. To identify ARX interacting proteins, we performed an unbiased proteomics screen and identified several components of the Wnt/β-catenin signaling pathway, including β-catenin (CTNNB1), B-cell CLL/lymphoma 9 (BCL9) and leucine rich repeat flightless interacting protein 2 (LRRFIP2), in cortical progenitor cells. Our data show that ARX positively regulates Wnt/ β-catenin signaling and that the C-terminal domain of ARX interacts with the armadillo repeats in β-catenin to promote Wnt/β-catenin signaling. In addition, we found BCL9 and P300 also interact with ARX to modulate Wnt/β-catenin signaling. These data provide new insights into how ARX can uniquely regulate cortical neurogenesis, and connect the function of ARX with Wnt/β-catenin signaling.