A Sall1-NuRD interaction regulates multipotent nephron progenitors and is required for loop of Henle formation
A Sall1-NuRD interaction regulates multipotent nephron progenitors and is required for loop of Henle formation
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DOI：
10.1242/dev.148692
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发表时间：
2017-09-01
期刊：
影响因子：
4.6
通讯作者：
Rauchman, Michael
中科院分区：
文献类型：
--
作者：
Basta, Jeannine M.;Robbins, Lynn;Rauchman, Michael
适当数量的肾单位的形成需要在肾祖细胞自我更新和分化之间保持严格的平衡。调节肾祖细胞向肾小泡转变的分子途径还不是很清楚。在这里，我们展示了Sall1与核小体重塑和脱乙酰酶复合体(NuRD)相互作用，以抑制肾单位前体细胞的过早分化。在转基因小鼠(Delta SRM)体内阻断SALL1-NuRD导致肾祖细胞加速分化和双侧肾发育不全。突变肾脏的转录图谱显示了一种显著的模式，其中肾小球和近端小管谱系的基因要么没有变化，要么上调，而Henle环和远端小管谱系的基因下调。这些基因表达的全球变化伴随着突变的Delta SRM肾脏Henle肾单位节段THP、NKCC2和AQP1阳性环的显著减少。这些发现突显了SALL1-NuRD相互作用在调节SIX2阳性的多能肾祖细胞和Henle环形成中的重要作用。
The formation of the proper number of nephrons requires a tightly regulated balance between renal progenitor cell self-renewal and differentiation. The molecular pathways that regulate the transition from renal progenitor to renal vesicle are not well understood. Here, we show that Sall1interacts with the nucleosome remodeling and deacetylase complex (NuRD) to inhibit premature differentiation of nephron progenitor cells. Disruption of Sall1-NuRD in vivo in knock-in mice (Delta SRM) resulted in accelerated differentiation of nephron progenitors and bilateral renal hypoplasia. Transcriptional profiling of mutant kidneys revealed a striking pattern in which genes of the glomerular and proximal tubule lineages were either unchanged or upregulated, and those in the loop of Henle and distal tubule lineages were downregulated. These global changes in gene expression were accompanied by a significant decrease in THP-, NKCC2-and AQP1-positive loop of Henle nephron segments in mutant Delta SRM kidneys. These findings highlight an important function of Sall1-NuRD interaction in the regulation of Six2-positive multipotent renal progenitor cells and formation of the loop of Henle.