Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
Department of Genetics, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10660-10665. doi: 10.1073/pnas.1702914114. Epub 2017 Sep 18.
MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.
微小 RNA（miRNAs）通过抑制特定基因的表达来影响各种生物过程。在这里，我们描述了 miR-34/449 家族在上皮细胞分化过程中的一个重要功能。我们发现 miR-34/449 在体内抑制细胞周期机制，并促进细胞周期退出，从而允许上皮细胞分化。该 miRNA 家族的所有六个成员的组成性缺失会导致多个促进细胞周期的蛋白质去抑制，从而阻止上皮细胞退出细胞周期并进入静止状态。因此，几种组织（如呼吸道上皮和输卵管）中的运动性多纤毛形成受到强烈抑制。结果，缺乏 miR-34/449 的小鼠表现出不育以及严重的慢性气道疾病，导致出生后死亡。这些结果表明，miRNA 介导的细胞周期抑制对于允许上皮细胞分化是必需的。
