Origin and stepwise evolution of vertebrate lungs.

Summary

Cross-species single-cell and regulatory analyses show that much of the genetic program for lungs existed before the emergence of bony fish, with later acquisition of lung-specific enhancers and mammal-specific alveolar innovations. Alveolar type 1 cells are mammal-specific, and sfta2 deletion causes severe respiratory defects in mice, establishing function for a new lung gene.

Key Findings

• Single-cell analyses across vertebrates reveal conserved lung cell programs and trajectories despite organ absence in cartilaginous fishes.
• Many lung enhancers and lung-related gene coexpression patterns are present in cartilaginous fishes, indicating an ancestral regulatory foundation.
• Alveolar type 1 cells are mammal-specific, with mammal-specific genes (e.g., ager, sfta2) highly expressed in lungs.
• Functional deletion of sfta2 in mice causes severe respiratory defects, demonstrating essential gene function in mammalian lung.

Clinical Implications

While not immediately clinical, defining mammal-specific alveolar programs and essential genes (e.g., sfta2) may inform congenital lung disease mechanisms and regenerative strategies targeting alveolar cell types.

Limitations

• Exact species numbers and developmental stages per species are not detailed in the abstract
• Regulatory inferences from enhancer conservation require further causal testing across taxa

Future Directions

Dissect regulatory enhancer function across non-mammalian models; map lineage trajectories with spatial multi-omics; translate mammal-specific alveolar programs to inform lung regeneration and disease.