Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis.
Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis.
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DOI：
10.1038/ki.2014.406
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发表时间：
2015-06
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
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由Dicer1酶激活的microRNAs控制转录后基因的表达。DICER1在肾脏发生过程中具有重要的上皮作用，但其在肾脏发育过程中在基质细胞中的作用尚不清楚。为了研究这一点，我们灭活了肾基质细胞中的Dicer1。这导致肾脏发育不良，肾小管和血管系统分化异常，以及围产儿死亡。在突变肾脏中，参与基质细胞迁移和激活的基因受到抑制，参与上皮和内皮分化和成熟的基因也受到抑制。在基质特异性Dicer1突变体中，近端小管的极性始终是不正确的，远端小管的分化减弱，Henle环的伸长减弱，导致缺乏内髓和乳头。肾小球成熟和毛细血管环形成异常，而肾小管周毛细血管形成较晚，分支增强，管径增大。在Dicer1缺失的肾基质细胞中，与迁移、增殖和形态发生功能相关的因子包括α-平滑肌肌动蛋白、整合素-α8、-β1和WNT途径转录调控因子LEF1的表达减少。间质中DICER1突变导致不同的microRNAs表达缺失。其中，miR-214、-199a-5p和-199a-3p在体外调节基质细胞的功能，包括WNT途径的激活、迁移和增殖。因此，肾间质室的Dicer1活性调节关键的基质细胞功能，进而调节肾形成过程中肾单位和血管系统的分化。
MicroRNAs, activated by the enzyme Dicer1, control post-transcriptional gene expression. Dicer1 has important roles in the epithelium during nephrogenesis, but its function in stromal cells during kidney development is unknown. To study this we inactivated Dicer1 in renal stromal cells. This resulted in hypoplastic kidneys, abnormal differentiation of the nephron tubule and vasculature, and perinatal mortality. In mutant kidneys, genes involved in stromal cell migration and activation were suppressed as were those involved in epithelial and endothelial differentiation and maturation. Consistently, polarity of the proximal tubule was incorrect, distal tubule differentiation was diminished, and elongation of Henle’s loop attenuated resulting in lack of inner medulla and papilla in stroma-specific Dicer1 mutants. Glomerular maturation and capillary loop formation were abnormal while peritubular capillaries, with enhanced branching and increased diameter, formed later. In Dicer1-null renal stromal cells, expression of factors associated with migration, proliferation and morphogenic functions including α-smooth muscle actin, integrin-α8, -β1, and the WNT pathway transcriptional regulator LEF1 were reduced. Dicer1 mutation in stroma led to loss of expression of distinct microRNAs. Of these, miR-214, -199a-5p and -199a-3p regulate stromal cell functions ex vivo, including WNT pathway activation, migration and proliferation. Thus, Dicer1 activity in the renal stromal compartment regulates critical stromal cell functions that, in turn, regulate differentiation of the nephron and vasculature during nephrogenesis.
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13.6
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