Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways

The generation of the paraxial skeleton requires that commitment and differ entiation of skeletal progenitors is precisely coordinated during limb outg rowth. Several signaling molecules have been identified that are important in specifying the pattern of these skeletal primordia. Very little is known , however, about the mechanisms regulating the differentiation of limb mese nchyme into chondrocytes. Overexpression of RAR alpha in transgenic animals interferes with chondrogenesis and leads to appendicular skeletal defects (Cash, D.E,, C.B, Beck, K. Schughart, E, Linney: and T.M. Underhill. 1997. J. Cell Biol. 136:445-457). Further analysis of these animals shows that ex pression of the transgene in chondroprogenitors maintains a prechondrogenic phenotype and prevents chondroblast differentiation even in the presence o f BMPs, which are known stimulators of cartilage formation. Moreover, an RA R antagonist accelerates chondroblast differentiation as demonstrated by th e emergence of collagen type II-expressing cells much earlier than in contr ol or BMP-treated cultures. Addition of Noggin to limb mesenchyme cultures inhibits cartilage formation and the appearance of precartilaginous condens ations. In contrast, abrogation of retinoid signaling is sufficient to indu ce the expression of the chondroblastic phenotype in the presence of Noggin . These findings show that BMP and RAR-signaling pathways appear to operate independently to coordinate skeletal development, and that retinoid signal ing can function in a BMP-independent manner to induce cartilage formation. Thus, retinoid signaling appears to play a novel and unexpected role in sk eletogenesis by regulating the emergence of chondroblasts from skeletal pro genitors.