RRC ID 61919
Author Hata K, Nishimura R, Muramatsu S, Matsuda A, Matsubara T, Amano K, Ikeda F, Harley VR, Yoneda T.
Title Paraspeckle protein p54nrb links Sox9-mediated transcription with RNA processing during chondrogenesis in mice.
Journal J Clin Invest
Abstract The Sox9 transcription factor plays an essential role in promoting chondrogenesis and regulating expression of chondrocyte extracellular-matrix genes. To identify genes that interact with Sox9 in promoting chondrocyte differentiation, we screened a cDNA library generated from the murine chondrogenic ATDC5 cell line to identify activators of the collagen, type II, alpha 1 (Col2a1) promoter. Here we have shown that paraspeckle regulatory protein 54-kDa nuclear RNA-binding protein (p54nrb) is an essential link between Sox9-regulated transcription and maturation of Sox9-target gene mRNA. We found that p54nrb physically interacted with Sox9 and enhanced Sox9-dependent transcriptional activation of the Col2a1 promoter. In ATDC5 cells, p54nrb colocalized with Sox9 protein in nuclear paraspeckle bodies, and knockdown of p54(nrb) suppressed Sox9-dependent Col2a1 expression and promoter activity. We generated a p54nrb mutant construct lacking RNA recognition motifs, and overexpression of mutant p54nrb in ATDC5 cells markedly altered the appearance of paraspeckle bodies and inhibited the maturation of Col2a1 mRNA. The mutant p54nrb inhibited chondrocyte differentiation of mesenchymal cells and mouse metatarsal explants. Furthermore, transgenic mice expressing the mutant p54nrb in the chondrocyte lineage exhibited dwarfism associated with impairment of chondrogenesis. These data suggest that p54nrb plays an important role in the regulation of Sox9 function and the formation of paraspeckle bodies during chondrogenesis.
Volume 118(9)
Pages 3098-108
Published 2008-9-1
DOI 10.1172/JCI31373
PMID 18677406
PMC PMC2491455
MeSH Amino Acid Motifs Animals Cell Differentiation Chondrogenesis / genetics* Gene Expression Regulation HeLa Cells High Mobility Group Proteins / metabolism* Humans Mice Models, Biological Mutation Nuclear Matrix-Associated Proteins / metabolism Nuclear Matrix-Associated Proteins / physiology* Promoter Regions, Genetic RNA / chemistry RNA / metabolism* RNA-Binding Proteins / metabolism RNA-Binding Proteins / physiology* SOX9 Transcription Factor Transcription Factors / metabolism* Transcription, Genetic
IF 11.864
Human and Animal Cells ATDC5(RCB0565) 10T1/2(RCB0247)