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Published 3 July 2006. doi:10.1083/jcb.200604150
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 1, 101-113
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Article

 BMP action in skeletogenesis involves attenuation of retinoid signaling

Lisa M. Hoffman1, Kamal Garcha2, Konstantina Karamboulas2, Matthew F. Cowan2, Linsay M. Drysdale1, William A. Horton3, and T. Michael Underhill1,2

1 Department of Physiology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1
2 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
3 Shriners Children's Hospital, Portland, OR 97239

Correspondence to T. Michael Underhill: tunderhi{at}interchange.ubc.ca

The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.

K. Garcha, K. Karamboulas, and M.F. Cowan contributed equally to this paper.

Abbreviations used in this paper: atRA, all-trans RA; BMP, bone morphogenetic protein; BMPR, BMP receptor; DEAB, diethyl aminobenzaldehyde; E, embryonic age; GDF, growth and differentiation factor; IDR, interdigital region; RA, retinoic acid; RAR, RA receptor; RARE, RA response element; Tp, distal tip; WL, whole limb.


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