Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Stem Cells. 2010 Jul;28(7):1260-9. doi: 10.1002/stem.455.
Dicer is an RNase III enzyme essential for microRNA maturation. Dicer ablation in diverse tissues has been shown to block tissue differentiation, induce cell apoptosis, impair specialized cellular function, and perturb organ structures. To gain insight into the role of microRNAs in prostate tissue function and homeostasis, we conditionally disrupted Dicer activity in the mouse prostate using an ARR2PB-Cre. We demonstrated that Dicer activity is disrupted in both prostatic basal/stem cells and differentiated luminal cells. Dicer knockout murine prostates are smaller in size and mass and develop epithelial hypotrophy in ventral prostates by 4 months. Dicer ablation induces increased apoptosis in the prostate, predominantly in the differentiated luminal cells. Paradoxically, a concurrent increase in proliferation is observed in both basal/stem cells and luminal cells, presumably due to compensatory growth of the cells devoid of homologous recombination in response to the elevated cellular apoptosis. We have previously shown that Lin(CD31CD45Ter119)(-)Sca-1(+)CD49f(high) (LSC) cells enrich for prostate stem cell activity. Through proliferation and differentiation, some LSC cells are capable of forming prostate spheres composed of cells at various stages of differentiation. Although LSC cells were expanded by threefold in Dicer knockout mice, the sphere-forming units of Dicer knockout prostate cells decreased by more than half compared with wild-type cells. In addition, most prostate spheres in the Dicer knockout culture were derived from cells that did not undergo homologous recombination. Our results demonstrate a critical role of microRNAs for the proliferative capacity of prostate stem cells and the maintenance of prostate homeostasis.
Dicer 是一种 RNase III 酶，对 microRNA 的成熟至关重要。在多种组织中敲除 Dicer 已被证明会阻止组织分化、诱导细胞凋亡、损害特化细胞功能以及扰乱器官结构。为了深入了解 microRNAs 在前列腺组织功能和稳态中的作用，我们使用 ARR2PB-Cre 在小鼠前列腺中条件性地破坏了 Dicer 的活性。我们证明 Dicer 活性在前列腺的基底/干细胞和分化的腔细胞中均被破坏。Dicer 敲除的小鼠前列腺体积较小且质量较小，并且在 4 个月时前叶前列腺的上皮细胞出现萎缩。Dicer 缺失会导致前列腺中的细胞凋亡增加，主要发生在分化的腔细胞中。矛盾的是，在基底/干细胞和腔细胞中观察到细胞增殖增加，这可能是由于缺乏同源重组的细胞为了应对细胞凋亡增加而进行代偿性生长。我们之前已经表明，Lin(CD31CD45Ter119)(-)Sca-1(+)CD49f(high)（LSC）细胞富集了前列腺干细胞活性。通过增殖和分化，一些 LSC 细胞能够形成包含不同分化阶段细胞的前列腺球体。尽管 Dicer 敲除小鼠中的 LSC 细胞扩增了三倍，但与野生型细胞相比，Dicer 敲除前列腺细胞的球体形成单位减少了一半以上。此外，Dicer 敲除培养物中的大多数前列腺球体来自未发生同源重组的细胞。我们的结果表明 microRNAs 对前列腺干细胞的增殖能力和前列腺稳态的维持具有重要作用。
