SOX9: dosage- and context-dependent functions in pancreatic development and β-cell biology

SOX9 is a highly conserved transcription factor (TF) belonging to the SRY-related HMG-box (SOX) family and the high-mobility group (HMG) class of DNA-binding proteins. SOX9 integrates structural flexibility, DNA-dependent dimerization, and context-specific cofactor interactions to orchestrate organogenesis. In the pancreas, SOX9 acts as a dosage-sensitive gatekeeper: high expression in multipotent progenitors maintains proliferation and prevents premature endocrine differentiation, while its timely downregulation is a prerequisite for NEUROG3 (NGN3) induction and β-cell maturation. Genetic and clinical data from campomelic dysplasia and mouse models reveal that both haploinsufficiency and dominant-negative SOX9 variants disrupt pancreatic morphogenesis and endocrine formation, whereas inappropriate SOX9 reactivation in adult β-cells under metabolic or hypoxic stress drives dedifferentiation and diabetes-like phenotypes. Recent work further demonstrates that low-level SOX9 expression persists in mature β-cells, where it regulates alternative splicing and stress adaptation, underscoring its lifelong importance for β-cell function. Despite these insights, SOX9 has not emerged as a diabetes susceptibility gene in genome-wide association studies, suggesting that SOX9-related β-cell failure is primarily driven by rare, severe mutations and dysregulated expression rather than common variants. This review synthesizes current understanding of SOX9's multifaceted roles across pancreatic development and adult β-cell biology, highlighting conserved mechanisms established through mouse genetics, species-specific considerations for translating findings to humans, and emerging opportunities for therapeutic intervention targeting SOX9-dependent pathways to preserve β-cell function and identity in diabetes.