Sall1 Maintains Nephron Progenitors and Nascent Nephrons by Acting as Both an Activator and a Repressor
Sall1 Maintains Nephron Progenitors and Nascent Nephrons by Acting as Both an Activator and a Repressor
复制标题
DOI：
10.1681/asn.2013080896
复制
发表时间：
2014-11-01
影响因子：
13.6
通讯作者：
Nishinakamura, Ryuichi
中科院分区：
文献类型：
--
作者：
Kanda, Shoichiro;Tanigawa, Shunsuke;Nishinakamura, Ryuichi
肾祖细胞平衡的自我更新和分化对肾脏发育至关重要，部分受转录因子SIX2控制，SIX2拮抗经典的Wnt信号介导的分化。作为一种核因子，SALL1在SIX2阳性的祖细胞和分化的新生肾单位中表达，对肾脏的形成是必不可少的。然而，SAL 11的分子功能和靶点，特别是在肾单位祖细胞中的功能和靶点仍不清楚。在这里，我们报告了SIX2阳性的肾单位祖细胞中SALL1的缺失导致小鼠肾单位严重枯竭和分化肾单位的凋亡。对带有可诱导SALL1缺失的小鼠的分析表明，SALL1激活了祖细胞中表达的基因，而抑制了分化肾单位中表达的基因。SALL1和SIX2共占多个祖细胞相关基因座，SALL1与SIX2生化结合。相反，SAL不与SIX2抑制的Wnt4位点结合。SALL1介导的抑制作用也不依赖于其与DNA的结合。因此，SAL11通过一种与SIX2部分重叠但不同于SIX2的独特机制维持肾单位祖细胞及其衍生物：SALL1激活SIX2阳性肾祖细胞的祖细胞相关基因，抑制SIX2阴性分化新生肾单位的基因表达。
The balanced self-renewal and differentiation of nephron progenitors are critical for kidney development and controlled, in part, by the transcription factor Six2, which antagonizes canonical Wnt signaling-mediated differentiation. A nuclear factor, Sall1 is expressed in Six2-positive progenitors as well as differentiating nascent nephrons, and it is essential for kidney formation. However, the molecular functions and targets of Sal 11, especially the functions and targets in the nephron progenitors, remain unknown. Here, we report that Sall1 deletion in Six2-positive nephron progenitors results in severe progenitor depletion and apoptosis of the differentiating nephrons in mice. Analysis of mice with an inducible Sall1 deletion revealed that Sall1 activates genes expressed in progenitors while repressing genes expressed in differentiating nephrons. Sall1 and Six2 co-occupied many progenitor-related gene loci, and Sall1 bound to Six2 biochemically. In contrast, Sal did not bind to the Wnt4 locus suppressed by Six2. Sall1-mediated repression was also independent of its binding to DNA. Thus, Sal 11 maintains nephron progenitors and their derivatives by a unique mechanism, which partly overlaps but is distinct from that of Six2: Sall1 activates progenitor-related genes in Six2-positive nephron progenitors and represses gene expression in Six2-negative differentiating nascent nephrons.