Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, New York, USA.
Kidney Int. 2011 Oct;80(7):719-30. doi: 10.1038/ki.2011.122. Epub 2011 May 4.
Micro-RNAs (miRNAs) are short (average 22 nucleotides) noncoding regulatory RNAs that inhibit gene expression by targeting complementary 3'-untranslated regions of protein-encoding mRNAs for translational repression or degradation. miRNAs play key roles in both the function and differentiation of many cell types. Drosha and Dicer, two RNAase III enzymes, function in a stepwise manner to generate a mature miRNA. Previous studies have shown that podocyte-specific deletion of Dicer during development results in proteinuric renal disease and collapsing glomerulopathy (CG); however, Dicer has functions other than the generation of miRNAs. Here we found that the podocyte-specific deletion of Drosha results in a similar phenotype to Dicer mutants, confirming that the Dicer mutant phenotype is due to the loss of miRNAs. Moreover, the inducible deletion of Drosha in 2- to 3-month-old mice (Tet-On system) resulted in CG. Thus, continuous generation of miRNAs are required for the normal function of mature podocytes and their loss leads to CG. Identifying these miRNAs may provide new insight into disease pathogenesis and novel therapeutic targets in various podocytopathies.
微 RNA（miRNAs）是短的（平均 22 个核苷酸）非编码调控 RNA，通过靶向蛋白质编码 mRNA 的互补 3'-非翻译区来抑制基因表达，从而实现翻译抑制或降解。miRNAs 在许多细胞类型的功能和分化中都发挥着关键作用。 Drosha 和 Dicer 是两种 RNAase III 酶，以逐步的方式发挥作用，产生成熟的 miRNA。先前的研究表明，在发育过程中，足细胞特异性缺失 Dicer 会导致蛋白尿性肾脏疾病和塌陷性肾小球病（CG）；然而，Dicer 的功能不仅仅是生成 miRNAs。在这里，我们发现足细胞特异性缺失 Drosha 会导致类似于 Dicer 突变体的表型，这证实了 Dicer 突变体的表型是由于 miRNAs 的缺失。此外，在 2-3 个月大的小鼠中诱导性地缺失 Drosha（Tet-On 系统）会导致 CG。因此，成熟足细胞的正常功能需要持续生成 miRNAs，而其缺失会导致 CG。鉴定这些 miRNAs 可能为各种足细胞病的发病机制和新的治疗靶点提供新的见解。
