GLI3

GLI3 is a gene that encodes a member of the GLI family of zinc finger transcription factors involved in Hedgehog signaling. The GLI3 protein can exist in two main forms: a full-length activator form and a truncated repressor form produced by proteolytic processing. In the absence of Hedgehog signaling, GLI3 is processed into GLI3R, which represses target gene expression. When Hedgehog signaling is active, processing is inhibited or reduced, allowing full-length GLI3 to accumulate and, in some contexts, function as a transcriptional activator, though GLI3 generally acts as a repressor compared with other GLI family members.

GLI3 regulates a set of Hedgehog-responsive genes by binding to GLI DNA-binding sites. Its activity is modulated by a network of proteins, including SUFU (Suppressor of Fused), which controls GLI3 localization and processing, and a kinase cascade involving PKA, CK1, and GSK3 that governs proteolysis. The balance between GLI3R and GLI3A contributes to the interpretation of Hedgehog signals during development and tissue patterning, particularly in the limb buds and developing brain.

Clinical significance of GLI3 mutations is well recognized. Haploinsufficient or mutated GLI3 causes Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome, both characterized by limb malformations such as polysyndactyly and craniofacial abnormalities, with broader effects on brain and organ development in some cases. GLI3-related disorders illustrate how precise regulation of transcriptional outputs from Hedgehog signaling shapes vertebrate development.

Research in GLI3 spans embryology, genetics, and disease, with ongoing work to delineate tissue-specific targets, interactions with other GLI proteins, and the impact of ciliary processing on GLI3 function.