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Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development.
- Source :
-
ELife [Elife] 2021 Oct 13; Vol. 10. Date of Electronic Publication: 2021 Oct 13. - Publication Year :
- 2021
-
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 (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.<br />Competing Interests: SR, JS, XY, AR, KA, PC, KI, MH, IM, AZ No competing interests declared<br /> (© 2021, Rankin et al.)
- Subjects :
- Aldehyde Dehydrogenase 1 Family metabolism
Animals
Base Sequence
Mesoderm embryology
Mice
Retinal Dehydrogenase metabolism
Sequence Alignment
T-Box Domain Proteins metabolism
Xenopus genetics
Xenopus metabolism
Xenopus Proteins metabolism
Xenopus laevis genetics
Xenopus laevis metabolism
Aldehyde Dehydrogenase 1 Family genetics
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Heart embryology
Lung embryology
Retinal Dehydrogenase genetics
T-Box Domain Proteins genetics
Xenopus embryology
Xenopus Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 34643182
- Full Text :
- https://doi.org/10.7554/eLife.69288