Unidirectional airflow in the avian lung enables gas exchange during both inhalation and exhalation. The underlying developmental process and how it deviates from that of the bidirectional mammalian lung are poorly understood. Sampling key developmental stages with multiscale 3D imaging and single-cell transcriptomics, we delineate morphogenic, molecular and cellular features that accommodate the unidirectional airflow in the chicken lung. Primary termini of hyper-elongated branches undergo proximal-short and distal-long fusions, forming parabronchi for air conduction. Through the parabronchial smooth muscle, neoform termini extend radially to form gas-exchanging alveoli. Supporting this radial alveologenesis, branch stalks halt their proximalization, defined by SOX9-SOX2 transition, and become SOX9low parabronchi. Primary and secondary vascular plexi interface with primary and neoform termini, respectively. Single-cell and Stereo-seq spatial transcriptomics reveal a third, chicken-specific alveolar cell type expressing KRT14, hereby named luminal cells. Luminal, alveolar type 2 and alveolar type 1 cells sequentially occupy concentric zones radiating from the parabronchial lumen. Our study explores the evolutionary space of lung diversification and lays the foundation for functional analysis of species-specific genetic determinants.

Retrotransposons (RTEs), which comprise nearly half of the mammalian genome, are silenced in adult somatic tissues but can be reactivated by physiological stimuli and in diseases. Here, we focus on adult regenerative tissues, particularly blood and skin, where RTE regulation requires a delicate balance between maintaining faithful silencing and harnessing physiological RTE activity to support stem cell maturation, stress responses, and interactions with tissue niches, and excessive reactivation can lead to stem cell exhaustion and tissue dysfunction. We summarize studies of RE-derived nucleic acids that, when aberrantly activated, engage innate immune sensors and trigger antiviral responses, linking RTE activity to inflammatory disorders. We further review experimental evidence in cancer, where RTE reactivation creates a battleground between antiviral defense and immune evasion, and emerging evidence suggesting that RTEs may mediate communication between peripheral tissues and the hematopoietic system. Finally, while experimental evidence is promising, clinical studies targeting RTE activity have produced mixed outcomes. We therefore conclude by highlighting the need for deeper mechanistic investigations.