Sall1, a causative gene for Townes-Brocks syndrome, enhances the canonical Wnt signaling by localizing to heterochromatin
Sall1, a causative gene for Townes-Brocks syndrome, enhances the canonical Wnt signaling by localizing to heterochromatin
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DOI：
10.1016/j.bbrc.2004.04.156
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发表时间：
2004-06-18
影响因子：
3.1
通讯作者：
Nishinakamura, R
中科院分区：
文献类型：
--
作者：
Sato, A;Kishida, S;Nishinakamura, R
Spalt（sal）基因家族在许多生物的发育过程中起着重要的调控作用。人SALL 1的突变导致常染色体显性遗传病，汤姆斯-布罗克斯综合征（TBS），并导致耳，四肢，肛门，肾脏和心脏异常。小鼠Sall 1的靶向缺失导致肾脏发育不全或严重发育不全。然而，Sall 1的分子机制在很大程度上仍然未知。在这里，我们报告说，Sall 1协同激活经典Wnt信号。Sall 1的转录活性与其核定位于点状核灶（近着丝粒异染色质）有关，但与其定位或与Wnt信号传导的核组分β-连环蛋白相关。相反，Sall 1的RNA干扰降低了经典Wnt信号传导的报告活性。TBS中常见的突变产生的N-末端截短的Sall 1干扰了天然Sall 1在异染色质中的定位，并且还下调了天然Sall 1对Wnt信号的协同转录增强。因此，我们提出了一种新的Wnt信号激活机制，即Sall 1的异染色质定位。(C)2004年爱思唯尔公司All rights reserved.
The Spalt (sal) gene family plays an important role in regulating developmental processes of many organisms. Mutations of human SALL1 cause the autosomal dominant disorder, Townes-Brocks syndrome (TBS), and result in ear, limb, anal, renal, and heart anomalies. Targeted deletion of mouse Sall1 results in kidney agenesis or severe dysgenesis. Molecular mechanisms of Sall1, however, have remained largely unknown. Here we report that Sall1 synergistically activates canonical Wnt signaling. The transcriptional activity of Sall1 is related to its nuclear localization to punctate nuclear foci (pericentromeric heterochromatin), but not to its localization or association with beta-catenin, the nuclear component of Wnt signaling. In contrast, the RNA interference of Sall1 reduces reporter activities of canonical Wnt signaling. The N-terminal truncated Sall1, produced by mutations often found in TBS, disturbs localization of native Sall1 to heterochromatin, and also down-regulates the synergistic transcriptional enhancement for Wnt signal by native Sall1. Thus, we propose a new mechanism for Wnt signaling activation, that is the heterochromatin localization of Sall1. (C) 2004 Elsevier Inc. All rights reserved.