GLI3 is a dual-function transcription factor in the sonic hedgehog (Shh) pathway that acts as both an activator (GLI3A from full-length GLI3) and a repressor (GLI3R from C-terminally truncated forms) 1. The balance between these two forms, rather than individual gradient levels, specifies limb digit number and identity 2. Mechanistically, GLI3 is phosphorylated by the ciliary kinase DYRK2 on conserved serine residues, promoting its dissociation from the suppressor SUFU and nuclear translocation to regulate Hh signaling 3. Beyond limb development, GLI3 is essential for cortical fate establishment in human brain development, regulating dorsoventral patterning through direct targets like HES4/5, and controlling ganglionic eminence diversification 4. GLI3 participates in an ERK-BMP7-GLI3R-SHH positive feedback loop central to cortical neurogenesis 5. Clinically, GLI3 mutations cause multiple syndromes including Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), and various polydactyly forms, with mutation location determining phenotype severity 1. Notably, GLI3 also functions as a transcriptional regulator in disease contexts, including gastric cancer predisposition through USP47 regulation 6.