Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation
Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation
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DOI：
10.1242/dev.089649
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发表时间：
2013-05-01
期刊：
影响因子：
4.6
通讯作者：
Yi, Rui
中科院分区：
文献类型：
--
作者：
Jackson, Sarah J.;Zhang, Zhaojie;Yi, Rui
microRNAs（miRNAs）在干细胞分化过程中起重要作用。然而，干细胞分化过程中miRNA诱导的精确动力学尚未可视化，miRNA执行其功能的分子机制仍不清楚。使用高分辨率原位杂交结合小鼠皮肤中的细胞谱系和增殖标记物，我们表明miR-203在滤泡间祖细胞的不对称细胞分裂后在分化的子细胞中被转录激活。一旦被诱导，miR-203在6小时内迅速促进细胞周期退出并消除祖细胞的自我更新。通过诱导型小鼠模型，我们确定了许多miR-203体内靶点，这些靶点高度富集于细胞周期和细胞分裂的调节以及对DNA损伤的响应。重要的是，miR-203对包括p63、Skp 2和Msi 2在内的单个靶点的共抑制是其促进细胞周期退出和抑制长期增殖的功能所必需的。总之，我们的研究结果揭示了miR-203对自我更新程序的快速和广泛的影响，并为miR-203在表皮分化过程中的有效作用提供了机制见解。这些结果也应该有助于了解miR-203在皮肤癌发生中的作用。
MicroRNAs (miRNAs) play important roles in differentiation of stem cells. However, the precise dynamics of miRNA induction during stem cell differentiation have not been visualized and molecular mechanisms through which miRNAs execute their function remain unclear. Using high-resolution in situ hybridization together with cell lineage and proliferation markers in mouse skin, we show that miR-203 is transcriptionally activated in the differentiating daughter cells upon the asymmetric cell division of interfollicular progenitor cells. Once induced, miR-203 rapidly promotes the cell cycle exit within 6 hours and abolishes self-renewal of the progenitor cells. With an inducible mouse model, we identify numerous miR-203 in vivo targets that are highly enriched in regulation of cell cycle and cell division, as well as in response to DNA damage. Importantly, co-suppression of individual targets, including p63, Skp2 and Msi2 by miR-203 is required for its function of promoting the cell cycle exit and inhibiting the long-term proliferation. Together, our findings reveal the rapid and widespread impact of miR-203 on the self-renewal program and provide mechanistic insights into the potent role of miR-203 during the epidermal differentiation. These results should also contribute to understanding the role of miR-203 in the development of skin cancer.