BMP action in skeletogenesis involves attenuation of retinoid signaling

J Cell Biol. 2006 Jul 3;174(1):101-13. doi: 10.1083/jcb.200604150.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / pharmacology
  • Chondrocytes / metabolism
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / physiology
  • Limb Buds
  • Mice
  • Organ Culture Techniques
  • Osteogenesis / physiology*
  • Oxygenases / genetics
  • Oxygenases / metabolism*
  • Phenotype
  • Receptors, Retinoic Acid / drug effects
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinal Dehydrogenase
  • Retinoids / physiology*
  • Signal Transduction / physiology*

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • Receptors, Retinoic Acid
  • Retinoids
  • Cytochrome P-450 Enzyme System
  • Oxygenases
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • Aldh1a2 protein, mouse
  • Retinal Dehydrogenase