Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

Elife. 2021 Oct 13;10:e69288. doi: 10.7554/eLife.69288.


The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using Xenopus and mouse embryos, we establish molecular links between Tbx5 and retinoic acid (RA) signaling in the mesoderm and between RA signaling and sonic hedgehog expression in the endoderm to unveil a conserved RA-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary (CP) development. We demonstrate that Tbx5 directly maintains expression of aldh1a2, the RA-synthesizing enzyme, in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module to restrict FGF activity to the anterior. We find that Tbx5/Aldh1a2-dependent RA signaling directly activates shh transcription in the adjacent foregut endoderm through a conserved MACS1 enhancer. Hedgehog signaling coordinates with Tbx5 in the mesoderm to activate expression of wnt2/2b, which induces pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing CP evolution and birth defects.

Keywords: Tbx5 transcription factor; Xenopus; cardiopulmonary; developmental biology; genetics; genomics; lung development; mouse; retinoic acid; xenopus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Dehydrogenase 1 Family / genetics*
  • Aldehyde Dehydrogenase 1 Family / metabolism
  • Animals
  • Base Sequence
  • Gene Expression Regulation, Developmental*
  • Gene Regulatory Networks*
  • Heart / embryology*
  • Lung / embryology*
  • Mesoderm / embryology
  • Mice
  • Retinal Dehydrogenase / genetics*
  • Retinal Dehydrogenase / metabolism
  • Sequence Alignment
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism
  • Xenopus / embryology*
  • Xenopus / genetics
  • Xenopus / metabolism
  • Xenopus Proteins / genetics*
  • Xenopus Proteins / metabolism
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism


  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Xenopus Proteins
  • Aldehyde Dehydrogenase 1 Family
  • Aldh1a2 protein, mouse
  • Retinal Dehydrogenase
  • aldh1a2 protein, Xenopus

Associated data

  • GEO/GSE167207
  • GEO/GSE75077
  • GEO/GSE126128
  • GEO/GSE136689
  • GEO/GSE139803
  • GEO/GSE104840
  • GEO/GSE54471