miR-200c regulates FGFR-dependent epithelial proliferation via Vldlr during submandibular gland branching morphogenesis
miR-200c regulates FGFR-dependent epithelial proliferation via Vldlr during submandibular gland branching morphogenesis
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DOI：
10.1242/dev.070151
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发表时间：
2012-01-01
期刊：
影响因子：
4.6
通讯作者：
Hoffman, Matthew P.
中科院分区：
文献类型：
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作者：
Rebustini, Ivan T.;Hayashi, Toru;Hoffman, Matthew P.
在器官形态发生过程中，上皮细胞增殖的调节对于正常发育至关重要，因为调节异常与肿瘤形成相关。非编码microRNAs（miRNAs），如miR-200 c，是参与癌症的基因的转录后调节因子。然而，miR-200 c在正常发育过程中的作用尚不清楚。我们筛选了在小鼠发育中的下颌下腺（SMG）中表达的miRNAs，发现miR-200 c在上皮端芽中积累。使用功能丧失和功能获得，我们证明了miR-200 c在SMG形态发生期间减少上皮增殖。为了确定其机制，我们预测了miR-200 c靶基因，并证实了它们在SMG发育过程中的表达。我们发现miR-200 c靶向极低密度脂蛋白受体（Vldlr）及其配体reelin，这出乎意料地调节FGFR依赖性上皮细胞增殖。因此，我们证明miR-200 c通过Vldlr依赖性机制在分支形态发生期间影响FGFR介导的上皮增殖。miR-200 c和Vldlr可能是腺修复或再生过程中控制上皮形态发生的新靶点。
The regulation of epithelial proliferation during organ morphogenesis is crucial for normal development, as dysregulation is associated with tumor formation. Non-coding microRNAs (miRNAs), such as miR-200c, are post-transcriptional regulators of genes involved in cancer. However, the role of miR-200c during normal development is unknown. We screened miRNAs expressed in the mouse developing submandibular gland (SMG) and found that miR-200c accumulates in the epithelial end buds. Using both loss- and gain-of-function, we demonstrated that miR-200c reduces epithelial proliferation during SMG morphogenesis. To identify the mechanism, we predicted miR-200c target genes and confirmed their expression during SMG development. We discovered that miR-200c targets the very low density lipoprotein receptor (Vldlr) and its ligand reelin, which unexpectedly regulate FGFR-dependent epithelial proliferation. Thus, we demonstrate that miR-200c influences FGFR-mediated epithelial proliferation during branching morphogenesis via a Vldlr-dependent mechanism. miR-200c and Vldlr may be novel targets for controlling epithelial morphogenesis during glandular repair or regeneration.