Dynamics of BMP signaling in limb bud mesenchyme and polydactyly

Dev Biol. 2014 Sep 15;393(2):270-281. doi: 10.1016/j.ydbio.2014.07.003. Epub 2014 Jul 14.

Abstract

Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis.

Keywords: BMP; Chondrogenesis; FGF; Gremlin; Limb development; Polydactyly; Sox9.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Bone Morphogenetic Protein 2 / antagonists & inhibitors
  • Bone Morphogenetic Protein 2 / genetics*
  • Bone Morphogenetic Protein 4 / antagonists & inhibitors
  • Bone Morphogenetic Protein 4 / genetics*
  • Bone Morphogenetic Protein 7 / antagonists & inhibitors
  • Bone Morphogenetic Protein 7 / genetics*
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Morphogenetic Proteins / genetics
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Chondrogenesis / genetics
  • Cytokines
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation, Developmental
  • Hindlimb / embryology
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Limb Buds / embryology*
  • Mesoderm / embryology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Polydactyly / embryology
  • Polydactyly / genetics*
  • SOX9 Transcription Factor / biosynthesis
  • Signal Transduction / genetics

Substances

  • Bmp2 protein, mouse
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • Cktsf1b1 protein, mouse
  • Cytokines
  • Grem1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • bmp7 protein, mouse
  • Fibroblast Growth Factors