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© The Rockefeller University Press, 0021-9525/2000//679 $5.00
The Journal of Cell Biology, Volume 148, Number 4, , 2000 679-690

Original Article

Regulation of Skeletal Progenitor Differentiation by the Bmp and Retinoid Signaling Pathways



Andrea D. Westonb, Vicki Rosenc, Roshantha A.S. Chandraratnad, and T. Michael Underhilla,b

a Division of Oral Biology, School of Dentistry
b Department of Physiology, Faculty of Medicine & Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
c Genetics Institute Inc., Cambridge, Massachusetts 02140
d Retinoid Research Group, Allergan Pharmaceuticals, Irvine, California 92623
School of Dentistry, Faculty of Medicine & Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada.(519) 661-2111, ext

The generation of the paraxial skeleton requires that commitment and differentiation of skeletal progenitors is precisely coordinated during limb outgrowth. 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 mesenchyme into chondrocytes. Overexpression of RAR{alpha} in transgenic animals interferes with chondrogenesis and leads to appendicular skeletal defects (Cash, D.E., C.B. Bock, K. Schughart, E. Linney, and T.M. Underhill. 1997. J. Cell Biol. 136:445–457). Further analysis of these animals shows that expression of the transgene in chondroprogenitors maintains a prechondrogenic phenotype and prevents chondroblast differentiation even in the presence of BMPs, which are known stimulators of cartilage formation. Moreover, an RAR antagonist accelerates chondroblast differentiation as demonstrated by the emergence of collagen type II–expressing cells much earlier than in control or BMP-treated cultures. Addition of Noggin to limb mesenchyme cultures inhibits cartilage formation and the appearance of precartilaginous condensations. In contrast, abrogation of retinoid signaling is sufficient to induce 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 signaling can function in a BMP-independent manner to induce cartilage formation. Thus, retinoid signaling appears to play a novel and unexpected role in skeletogenesis by regulating the emergence of chondroblasts from skeletal progenitors.

Key Words: retinoic acid • chondrogenesis • bone morphogenetic proteins • limb development • Noggin

© 2000 The Rockefeller University Press

Abbreviations used in this paper: BMPs, bone morphogenetic proteins; E, embryonic age; GDF, growth differentiation factor; IDR, interdigital region; RA, retinoic acid; RARs, retinoic acid receptors; TGF, transforming growth factor; RXRs, retinoid X receptors.


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