Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

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 demon...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (6), p.1949-1954
Main Authors: Kobayashi, Tatsuya, Lu, Jun, Cobb, Bradley S, Rodda, Stephen J, McMahon, Andrew P, Schipani, Ernestina, Merkenschlager, Matthias, Kronenberg, Henry M
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological Sciences
Bone Development
Bones
Cartilage
Cell Differentiation - physiology
Cell Proliferation
Chondrocytes
Chondrocytes - cytology
DNA Primers
Embryology
Epiphyses
Gene expression
Gene Expression Profiling
Gene expression regulation
Genes
Messenger RNA
Mice
Mice, Transgenic
MicroRNA
MicroRNAs - genetics
Reverse Transcriptase Polymerase Chain Reaction
Ribonuclease III - metabolism
Ribonuclease III - physiology
Ribonucleic acid
RNA
Rodents
Skeletal development
Skeletal system
Transgenic animals
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0707900105