Tbx5 drives aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development
- Cincinnati Children's Hospital Medical Center, United States
- University of Chicago, United States
Abstract
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 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 cardiopulmonary evolution and birth defects.
Data availability
ChIP-seq data generated in this study is available from the Gene Expression Omnibus (GEO) accession number GSE167207.
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TBX5 ChIP from the Fetal LungNCBI Gene Expression Omnibu GSE167207.
Article and author information
Author details
Michael J Herriges
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD093363)
- Aaron M Zorn
National Heart, Lung, and Blood Institute (R01HL092153)
- Ivan P Moskowitz
National Heart, Lung, and Blood Institute (R01HL124836)
- Ivan P Moskowitz
National Institute of General Medical Sciences (T32GM007183)
- Jeffrey D Steimle
National Heart, Lung, and Blood Institute (T32HL007381)
- Jeffrey D Steimle
National Heart, Lung, and Blood Institute (T32HL007381)
- Ariel B Rydeen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Edward E Morrisey, University of Pennsylvania, United States
Ethics
Animal experimentation: Mouse and Xenopus experiments were performed according to Institutional Animal Care and Use Committee (IACUC) protocols (University of Chicago protocol 71737; Cincinnati Children's Hospital protocol 2019-0053).
Version history
- Received: April 10, 2021
- Preprint posted: April 11, 2021 (view preprint)
- Accepted: September 23, 2021
- Accepted Manuscript published: October 13, 2021 (version 1)
- Version of Record published: October 29, 2021 (version 2)
Copyright
© 2021, Rankin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tbx5 drives aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development
eLife 10:e69288.
https://doi.org/10.7554/eLife.69288
