Kobayashi Tatsuya, Lu Jun, Cobb Bradley S, Rodda Stephen J, McMahon Andrew P, Schipani Ernestina, Merkenschlager Matthias, Kronenberg Henry M
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1949-54. doi: 10.1073/pnas.0707900105. Epub 2008 Jan 31.
Small noncoding RNAs, microRNAs (miRNAs), bind to messenger RNAs through base pairing to suppress gene expression. Despite accumulating evidence that miRNAs play critical roles in various biological processes across diverse organisms, their roles in mammalian skeletal development have not been demonstrated. Here, we show that Dicer, an essential component for biogenesis of miRNAs, is essential for normal skeletal development. Dicer-null growth plates show a progressive reduction in the proliferating pool of chondrocytes, leading to severe skeletal growth defects and premature death of mice. The reduction of proliferating chondrocytes in Dicer-null growth plates is caused by two distinct mechanisms: decreased chondrocyte proliferation and accelerated differentiation into postmitotic hypertrophic chondrocytes. These defects appear to be caused by mechanisms downstream or independent of the Ihh-PTHrP signaling pathway, a pivotal signaling system that regulates chondrocyte proliferation and differentiation. Microarray analysis of Dicer-null chondrocytes showed limited expression changes in miRNA-target genes, suggesting that, in the majority of cases, chondrocytic miRNAs do not directly regulate target RNA abundance. Our results demonstrate the critical role of the Dicer-dependent pathway in the regulation of chondrocyte proliferation and differentiation during skeletal development.
小型非编码RNA，即微小RNA（miRNA），通过碱基配对与信使RNA结合以抑制基因表达。尽管越来越多的证据表明miRNA在不同生物体的各种生物学过程中发挥关键作用，但其在哺乳动物骨骼发育中的作用尚未得到证实。在此，我们表明Dicer是miRNA生物合成的必需成分，对正常骨骼发育至关重要。缺乏Dicer的生长板中软骨细胞增殖池逐渐减少，导致严重的骨骼生长缺陷和小鼠过早死亡。缺乏Dicer的生长板中增殖软骨细胞的减少是由两种不同机制引起的：软骨细胞增殖减少和加速分化为有丝分裂后肥大软骨细胞。这些缺陷似乎是由Ihh-PTHrP信号通路下游或独立于该信号通路的机制引起的，Ihh-PTHrP信号通路是调节软骨细胞增殖和分化的关键信号系统。对缺乏Dicer的软骨细胞进行微阵列分析显示，miRNA靶基因的表达变化有限，这表明在大多数情况下，软骨细胞miRNA并不直接调节靶RNA丰度。我们的结果证明了Dicer依赖性途径在骨骼发育过程中调节软骨细胞增殖和分化的关键作用。
