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 beta-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 beta-cells under metabolic or hypoxic stress drives dedifferentiation and diabetes-like phenotypes. Recent work further demonstrates that low-level SOX9 expression persists in mature beta-cells, where it regulates alternative splicing and stress adaptation, underscoring its lifelong importance for beta-cell function. Despite these insights, SOX9 has not emerged as a diabetes susceptibility gene in genome-wide association studies, suggesting that SOX9-related beta-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 beta-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 beta-cell function and identity in diabetes.