Unraveling the SOX11-IGF2 signaling axis in early lung development: implications for lung disease

The essential function of SOX11 in directing mammalian organogenesis is well-established. Nevertheless, the intricate signaling network it orchestrates, especially during early lung development, remains poorly understood. This study delves into the role of SOX11 in early lung development using a Sox11 knockout mouse model. Developmental analyses reveal that pulmonary malformations emerge during branching morphogenesis, characterized by defective epithelial-mesenchymal condensation and reduced intercellular spacing. By E18.5, Sox11^-/- mice exhibit disrupted bronchial morphogenesis and impaired alveolar epithelial maturation. RNA sequencing reveals Igf2 as a downregulated gene, with pathways related to lung development displaying significant enrichment. IGF2 knockdown in MLE12 and A549 cells induces abnormalities in apoptosis, proliferation, migration, and polarity. ChIP-seq analyses in A549 and MRC5 cells further reveal that SOX11 regulates IGF2 without direct binding, suggesting a sophisticated regulatory network. Our findings establish the critical role of "SOX11-IGF2" signaling in early lung morphogenesis, offering theoretical insights into human lung developmental and cancers disorders.