Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Development. 2012 Aug;139(16):3021-31. doi: 10.1242/dev.080127. Epub 2012 Jul 4.
Genome-encoded microRNAs (miRNAs) provide a post-transcriptional regulatory layer that is important for pancreas development. However, how specific miRNAs are intertwined into the transcriptional network, which controls endocrine differentiation, is not well understood. Here, we show that microRNA-7 (miR-7) is specifically expressed in endocrine precursors and in mature endocrine cells. We further demonstrate that Pax6 is an important target of miR-7. miR-7 overexpression in developing pancreas explants or in transgenic mice led to Pax6 downregulation and inhibition of α- and β-cell differentiation, resembling the molecular changes caused by haploinsufficient expression of Pax6. Accordingly, miR-7 knockdown resulted in Pax6 upregulation and promoted α- and β-cell differentiation. Furthermore, Pax6 downregulation reversed the effect of miR-7 knockdown on insulin promoter activity. These data suggest a novel miR-7-based circuit that ensures precise control of endocrine cell differentiation.
基因组编码的 microRNAs (miRNAs) 提供了一个转录后调控层，对于胰腺发育非常重要。然而，特定的 miRNAs 如何与控制内分泌分化的转录网络交织在一起，目前还不是很清楚。在这里，我们表明 microRNA-7 (miR-7) 特异性地在内分泌前体细胞和成熟内分泌细胞中表达。我们进一步证明 Pax6 是 miR-7 的一个重要靶标。在胰腺外植体或转基因小鼠中过表达 miR-7 导致 Pax6 下调和 α-和 β-细胞分化的抑制，类似于 Pax6 半合子表达引起的分子变化。因此，miR-7 的敲低导致 Pax6 的上调并促进 α-和 β-细胞分化。此外，Pax6 的下调逆转了 miR-7 敲低对胰岛素启动子活性的影响。这些数据表明了一个新的基于 miR-7 的回路，它确保了内分泌细胞分化的精确控制。
