A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification

Cell Rep. 2016 Jun 28;16(1):66-78. doi: 10.1016/j.celrep.2016.05.060. Epub 2016 Jun 16.


Organogenesis of the trachea and lungs requires a complex series of mesoderm-endoderm interactions mediated by WNT, BMP, retinoic acid (RA), and hedgehog (Hh), but how these pathways interact in a gene regulatory network is less clear. Using Xenopus embryology, mouse genetics, and human ES cell cultures, we identified a conserved signaling cascade that initiates respiratory lineage specification. We show that RA has multiple roles; first RA pre-patterns the lateral plate mesoderm and then it promotes Hh ligand expression in the foregut endoderm. Hh subsequently signals back to the pre-patterned mesoderm to promote expression of the lung-inducing ligands Wnt2/2b and Bmp4. Finally, RA regulates the competence of the endoderm to activate the Nkx2-1+ respiratory program in response to these mesodermal WNT and BMP signals. These data provide insights into early lung development and a paradigm for how mesenchymal signals are coordinated with epithelial competence during organogenesis.

Keywords: Bmp; Hedgehog; Nkx2-1; Wnt; Xenopus; lung development; organogenesis; retinoic acid.

MeSH terms

  • Animals
  • Body Patterning*
  • Cell Differentiation
  • Cells, Cultured
  • Embryo, Mammalian / metabolism
  • Embryo, Nonmammalian / metabolism
  • Endoderm / embryology*
  • Endoderm / metabolism
  • Hedgehog Proteins / metabolism*
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Intestines / embryology
  • Ligands
  • Lung / embryology*
  • Lung / metabolism
  • Mesoderm / embryology*
  • Mesoderm / metabolism
  • Mice
  • Respiration
  • Signal Transduction*
  • Stem Cells / metabolism
  • Tretinoin / metabolism*
  • Wnt Proteins / metabolism
  • Xenopus Proteins / metabolism
  • Xenopus laevis


  • Hedgehog Proteins
  • Ligands
  • Wnt Proteins
  • Xenopus Proteins
  • Tretinoin