Interconnected heart and lungs, symbolizing the link between Tbx5 gene and cardiopulmonary development

Unlocking the Secrets of Heart and Lung Development: How a Single Gene Holds the Key

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Lena Voss in Science & Nature June 2025 • 4 min read.

"Scientists discover the pivotal role of the Tbx5 gene in coordinating the development of the heart and lungs, offering new insights into congenital diseases and evolutionary biology."


The transition from aquatic to terrestrial life marked a pivotal moment in vertebrate evolution, demanding significant adaptations in both the respiratory and cardiovascular systems. Lungs, the organs responsible for extracting oxygen from the air, and the heart, which pumps oxygenated blood throughout the body, had to evolve in a coordinated fashion to support this new lifestyle. This intricate co-development hinges on the seamless integration of cardiac and pulmonary structures, particularly the atrial septum, which separates oxygenated and deoxygenated blood within the heart.

For years, scientists have been working to understand how these vital systems develop in unison. One area of focus has been on the second heart field (SHF), also known as cardiopulmonary progenitors (CPPs). These cells are like master builders, giving rise to key structures in both the heart and lungs. Researchers have long suspected that transcription factors—proteins that control gene expression—within the SHF play a direct role in orchestrating this complex developmental process. The Tbx5 gene, crucial for cardiac septation, has always been in the spotlight, but the exact way it directs the morphogenesis has remained unclear.

Now, a groundbreaking study is challenging long-held assumptions about Tbx5, revealing that it doesn't directly drive heart development but acts as a key regulator in a sophisticated signaling network. This study uncovers the surprising role of Tbx5 in initiating lung development and coordinating the critical interplay between the developing heart and lungs.

TBX5: The Master Conductor of Cardiopulmonary Orchestration

Interconnected heart and lungs, symbolizing the link between Tbx5 gene and cardiopulmonary development

The study reveals that Tbx5 doesn't directly control heart morphogenesis. Instead, it orchestrates the production of Wnt ligands, signaling molecules that kickstart a bidirectional communication loop. This loop involves the cardiopulmonary mesoderm, the tissue that gives rise to the heart and lungs, and the foregut endoderm, which eventually forms the lining of the respiratory and digestive tracts. This signaling cascade is vital for specifying the pulmonary lineage and ensuring the proper formation of the atrial septum.

Researchers discovered that Tbx5 is essential for lung development in both mice and amphibians but not for the swim bladder, an organ found in fish that is considered evolutionarily related to the lungs. Further investigation revealed that Tbx5 acts non-cell-autonomously, meaning it doesn't directly act within the cells that form the lungs. Instead, it controls the expression of Wnt2 and Wnt2b in the cardiopulmonary mesoderm. These Wnt ligands then signal to the adjacent endoderm, instructing it to develop into the lung.

Here's a quick breakdown of the key findings:
  • Tbx5 directly activates Wnt2 and Wnt2b expression in the cardiopulmonary mesoderm.
  • This Wnt signaling is essential for initiating lung development in mammals and amphibians.
  • Tbx5 is required for proper Shh signaling, which plays a vital role in cardiac morphogenesis.
  • This intricate signaling loop is conserved across species, highlighting its evolutionary importance.
Further experiments showed that Tbx5 collaborates with Shh signaling, another crucial pathway, to drive lung morphogenesis. Mice with a deficiency in Tbx5, a model for Holt-Oram syndrome in humans, exhibited reduced mesodermal-to-endodermal Wnt signaling and subsequent endodermal-to-mesodermal Shh signaling. This disruption ultimately affected cardiac morphogenesis.

Implications for Understanding Congenital Diseases and Evolution

These findings provide a new framework for understanding the co-evolution of pulmonary and cardiac structures that was required for terrestrial life. It also sheds light on the underlying mechanisms of congenital heart defects like Holt-Oram syndrome. The discovery that Tbx5 initiates a mesoderm-endoderm-mesoderm signaling loop offers potential new avenues for therapeutic interventions targeting these conditions. By understanding the intricate choreography of heart and lung development, we can pave the way for better diagnostics, treatments, and ultimately, prevention of congenital diseases.

About this Article -

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Everything You Need To Know

1

What role does the Tbx5 gene play in coordinating heart and lung development?

The Tbx5 gene plays a pivotal role, not by directly driving heart development, but by acting as a key regulator in a sophisticated signaling network. It orchestrates the production of Wnt ligands, which kickstart a bidirectional communication loop involving the cardiopulmonary mesoderm and the foregut endoderm. This signaling cascade is vital for specifying the pulmonary lineage and ensuring the proper formation of the atrial septum.

2

How does Tbx5 influence lung development in different species, such as mice, amphibians, and fish?

The study revealed that Tbx5 is essential for lung development in both mice and amphibians. It controls the expression of Wnt2 and Wnt2b in the cardiopulmonary mesoderm, which then signal to the adjacent endoderm, instructing it to develop into the lung. This mechanism differs in fish, where the related swim bladder does not depend on Tbx5 in the same way.

3

How does a deficiency in the Tbx5 gene relate to congenital heart defects like Holt-Oram syndrome?

Holt-Oram syndrome is linked to deficiencies in Tbx5. Research indicates that reduced mesodermal-to-endodermal Wnt signaling and subsequent endodermal-to-mesodermal Shh signaling, resulting from Tbx5 deficiency, disrupts cardiac morphogenesis. Understanding this disruption offers insights into the underlying mechanisms of this congenital heart defect.

4

What is the evolutionary significance of Tbx5 in the context of the transition from aquatic to terrestrial life?

The transition from aquatic to terrestrial life required significant adaptations in both the respiratory and cardiovascular systems. The coordinated development of the lungs and the heart, particularly the atrial septum, was crucial. The Tbx5 gene plays a central role in coordinating these developments through a mesoderm-endoderm-mesoderm signaling loop, highlighting the gene's importance in the evolution of terrestrial vertebrates.

5

What are the potential therapeutic implications of understanding the Tbx5 signaling pathway in treating congenital diseases?

The discovery that Tbx5 initiates a mesoderm-endoderm-mesoderm signaling loop offers potential new avenues for therapeutic interventions targeting congenital heart defects. By understanding the intricate choreography of heart and lung development, we can pave the way for better diagnostics, treatments, and ultimately, prevention of congenital diseases.

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