RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation

Cell Rep. 2015 Aug 4;12(5):879-91. doi: 10.1016/j.celrep.2015.06.068. Epub 2015 Jul 23.


The retinoic acid (RA)- and β-catenin-signaling pathways regulate limb bud induction and initiation; however, their mechanisms of action are not understood and have been disputed. We demonstrate that both pathways are essential and that RA and β-catenin/TCF/LEF signaling act cooperatively with Hox gene inputs to directly regulate Tbx5 expression. Furthermore, in contrast to previous models, we show that Tbx5 and Tbx4 expression in forelimb and hindlimb, respectively, are not sufficient for limb outgrowth and that input from RA is required. Collectively, our data indicate that RA signaling and Tbx genes act in a coherent feed-forward loop to regulate Fgf10 expression and, as a result, establish a positive feedback loop of FGF signaling between the limb mesenchyme and ectoderm. Our results incorporate RA-, β-catenin/TCF/LEF-, and FGF-signaling pathways into a regulatory network acting to recruit cells of the embryo flank to become limb precursors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avian Proteins / genetics
  • Avian Proteins / metabolism*
  • Chick Embryo
  • Chickens
  • Gene Expression Regulation, Developmental / drug effects*
  • Limb Buds / cytology
  • Limb Buds / embryology*
  • Organogenesis / drug effects*
  • Signal Transduction / drug effects
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Tretinoin / pharmacology*


  • Avian Proteins
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Tretinoin