Jul 10, 2002

Requirement for RAR-mediated gene repression in skeletal progenitor differentiation

The Journal of Cell Biology
Andrea D WestonT Michael Underhill

Abstract

Chondrogenesis is a multistep process culminating in the establishment of a precisely patterned template for bone formation. Previously, we identified a loss in retinoid receptor-mediated signaling as being necessary and sufficient for expression of the chondroblast phenotype (Weston et al., 2000. J. Cell Biol. 148:679-690). Here we demonstrate a close association between retinoic acid receptor (RAR) activity and the transcriptional activity of Sox9, a transcription factor required for cartilage formation. Specifically, inhibition of RAR-mediated signaling in primary cultures of mouse limb mesenchyme results in increased Sox9 expression and activity. This induction is attenuated by the histone deacetylase inhibitor, trichostatin A, and by coexpression of a dominant negative nuclear receptor corepressor-1, indicating an unexpected requirement for RAR-mediated repression in skeletal progenitor differentiation. Inhibition of RAR activity results in activation of the p38 mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) pathways, indicating their potential role in the regulation of chondrogenesis by RAR repression. Accordingly, activation of RAR signaling, which attenuates differentiation, can be rescued by activat...Continue Reading

Mentioned in this Paper

Biochemical Pathway
Cyclic AMP-Responsive DNA-Binding Protein
Pyridines
Dominant-Negative Mutation
Thiophenes
Transfection
SOX9 gene
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 14
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole

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