Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development
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 mechanistic...
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eLife Sciences Publications Ltd
2021
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oai:doaj.org-article:ff23278fda4f49459f92c86f5c8b7d552021-11-26T11:14:31ZTbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development10.7554/eLife.692882050-084Xe69288https://doaj.org/article/ff23278fda4f49459f92c86f5c8b7d552021-10-01T00:00:00Zhttps://elifesciences.org/articles/69288https://doaj.org/toc/2050-084XThe 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.Scott A RankinJeffrey D SteimleXinan H YangAriel B RydeenKunal AgarwalPraneet ChaturvediKohta IkegamiMichael J HerrigesIvan P MoskowitzAaron M ZorneLife Sciences Publications LtdarticleXenopusretinoic acidcardiopulmonarylung developmentTbx5 transcription factormouseMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
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Xenopus retinoic acid cardiopulmonary lung development Tbx5 transcription factor mouse Medicine R Science Q Biology (General) QH301-705.5 |
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Xenopus retinoic acid cardiopulmonary lung development Tbx5 transcription factor mouse Medicine R Science Q Biology (General) QH301-705.5 Scott A Rankin Jeffrey D Steimle Xinan H Yang Ariel B Rydeen Kunal Agarwal Praneet Chaturvedi Kohta Ikegami Michael J Herriges Ivan P Moskowitz Aaron M Zorn Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development |
| description |
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. |
| format |
article |
| author |
Scott A Rankin Jeffrey D Steimle Xinan H Yang Ariel B Rydeen Kunal Agarwal Praneet Chaturvedi Kohta Ikegami Michael J Herriges Ivan P Moskowitz Aaron M Zorn |
| author_facet |
Scott A Rankin Jeffrey D Steimle Xinan H Yang Ariel B Rydeen Kunal Agarwal Praneet Chaturvedi Kohta Ikegami Michael J Herriges Ivan P Moskowitz Aaron M Zorn |
| author_sort |
Scott A Rankin |
| title |
Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development |
| title_short |
Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development |
| title_full |
Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development |
| title_fullStr |
Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development |
| title_full_unstemmed |
Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development |
| title_sort |
tbx5 drives aldh1a2 expression to regulate a ra-hedgehog-wnt gene regulatory network coordinating cardiopulmonary development |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/ff23278fda4f49459f92c86f5c8b7d55 |
| work_keys_str_mv |
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