Multifaceted role of Iroquois signaling in development and diseases

The Iroquois (Iro/Irx) gene family encodes transcription factors that belong to the Three-Amino-Acid Loop Extension-class homeodomain group, distinguished by a conserved Iro-box domain. Iroquois signaling is evolutionarily conserved from invertebrates to vertebrates and plays a vital role in embryonic development. In invertebrates, Iro/Irx genes control tissue compartmentalization, whereas in vertebrates, they regulate gastrulation, neural patterning, and organogenesis. These genes are typically organized in conserved genomic clusters under shared regulatory control, reflecting their coordinated expression and common evolutionary origins. Beyond development, dysregulation of Iroquois genes has been implicated in diverse human diseases. Iro/Irx genes are increasingly associated with congenital disorders, including congenital heart disease and neurodevelopmental abnormalities. Moreover, their emerging role in cancer biology has revealed context-dependent behavior, functioning as either tumor suppressors or oncogenes. Recent findings have also highlighted their potential as clinical biomarkers in neurological and neoplastic diseases. Given their broad developmental and pathological roles, Iroquois genes are gaining recognition as promising candidates for therapeutic targeting and molecular diagnostics. This review integrates their developmental functions with their disease associations to provide a comprehensive overview of the biological and clinical significance of Iroquois signaling.