MicroRNA-17∼92 Is Required for Nephrogenesis and Renal Function
MicroRNA-17∼92 Is Required for Nephrogenesis and Renal Function
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DOI：
10.1681/asn.2013040390
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发表时间：
2014-07-01
影响因子：
13.6
通讯作者：
Ho, Jacqueline
中科院分区：
文献类型：
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作者：
Marrone, April K.;Stolz, Donna B.;Ho, Jacqueline
肾元祖细胞中所有microrna （mirna）的缺失会导致这些细胞过早丢失，但特异性mirna在祖细胞中的作用尚未确定。在Feingold综合征患者的一个亚群中检测到MIR17HG簇（miR-17在小鼠中类似于92）的缺失，这是第一个与人类发育缺陷相关的miRNA突变。尽管MIR17HG在发育中的肾脏中表达，并且MYCN突变引起的Feingold综合征患者存在肾脏异常，但MIR17HG在多大程度上促进肾脏发育和功能仍不清楚。为了确定类似于92的miR-17的作用，我们在肾元祖细胞及其衍生物中产生了条件缺失类似于92的miR-17的小鼠。肾元祖细胞在小鼠体内得到保存；然而，这种缺失损害了祖细胞的增殖并减少了发育中的肾单位的数量。出生后，突变小鼠出现肾脏疾病的迹象，包括6周的蛋白尿，3个月的局灶性足细胞足突消退和肾小球硬化。综上所述，这些数据支持该miRNA簇在肾脏发育中的作用，特别是在肾元发育的调节中，并对成年小鼠的肾功能产生后续影响。
Deletion of all microRNAs (miRNAs) in nephron progenitors leads to premature loss of these cells, but the roles of specific miRNAs in progenitors have not been identified. Deletions in the MIR17HG cluster (miR-17 similar to 92 in mice), detected in a subset of patients with Feingold syndrome, represent the first miRNA mutations to be associated with a developmental defect in humans. Although MIR17HG is expressed in the developing kidney, and patients with Feingold syndrome caused by MYCN mutations have renal anomalies, it remains unclear to what extent MIR17HG contributes to renal development and function. To define the role of miR-17 similar to 92, we generated mice with a conditional deletion of miR-17 similar to 92 in nephron progenitors and their derivatives. The nephron progenitor population was preserved in these mice; however, this deletion impaired progenitor cell proliferation and reduced the number of developing nephrons. Postnatally, mutant mice developed signs of renal disease, including albuminuria by 6 weeks and focal podocyte foot process effacement and glomerulosclerosis at 3 months. Taken together, these data support a role for this miRNA cluster in renal development, specifically in the regulation of nephron development, with subsequent consequences for renal function in adult mice.