| Full Name | GLI Family Zinc Finger 3 |
| Gene Symbol | GLI3 |
| Chromosomal Location | 7p14.1 |
| NCBI Gene ID | [2737](https://www.ncbi.nlm.nih.gov/gene/2737) |
| OMIM | [165240](https://omim.org/entry/165240) |
| Ensembl | [ENSG00000106571](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000106571) |
| UniProt (Protein) | [P10071 (GLI3)](https://www.uniprot.org/uniprot/P10071) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), Greig Cephalopolysyndactyly, Pallister-Hall Syndrome, [Parkinson's Disease](/diseases/parkinsons-disease), Acrocallosal Syndrome |
GLI3 (GLI Family Zinc Finger 3) encodes a 1580 amino acid zinc finger transcription factor that functions as the principal transcriptional repressor of the Hedgehog (Hh) signaling pathway. While GLI1 acts solely as an activator and GLI2 is the primary activator, GLI3 predominantly operates as a repressor (GLI3R) that is proteolytically processed in the absence of Hedgehog signal. The ratio of full-length GLI3 activator (GLI3A) to truncated GLI3 repressor (GLI3R) — the GLI3A:GLI3R gradient — is the critical readout of Hedgehog morphogen signaling during neural patterning. GLI3 is essential for dorsal-ventral patterning of the neural tube, cortical development, and limb patterning, and its dysregulation has been implicated in neurodegenerative and neurodevelopmental disorders.
GLI3 spans approximately 276 kb on chromosome 7p14.1 and contains 15 exons encoding a 1580 amino acid protein. The genomic locus is one of the largest among transcription factor genes and contains a complex regulatory landscape including multiple long-range enhancers located in neighboring gene deserts. The cis-regulatory element ZRS (zone of polarizing activity regulatory sequence) located within intron 5 of the LMBR1 gene regulates limb-specific expression, while neural-specific enhancers within and flanking the GLI3 locus drive CNS expression.
In the developing nervous system, GLI3 is broadly expressed in dorsal and intermediate regions of the neural tube, where its repressor form (GLI3R) restricts ventral cell fates. Expression is particularly prominent in the developing cerebral cortex, where GLI3 regulates progenitor proliferation, cortical size, and dorsal-ventral specification. In the adult brain, GLI3 is expressed in the cortex, hippocampus, astrocytes, and adult neural stem cells of the SVZ. The Allen Brain Atlas shows widespread cortical expression with enrichment in frontal and parietal regions.
GLI3 is a bifunctional transcription factor with an architecture similar to GLI2:
The processing of GLI3 is the central regulatory event:
Upon pathway activation by SHH binding to PTCH1 and SMO activation, processing is inhibited, and full-length GLI3A accumulates to activate transcription. The GLI3A:GLI3R ratio thus translates graded Hedgehog morphogen concentrations into differential gene expression programs that specify distinct neuronal subtypes along the dorsal-ventral axis.
GLI3 mutations cause several neurodevelopmental syndromes:
In AD, altered GLI3 processing has been observed in cortical and hippocampal tissues. Increased GLI3R:GLI3A ratio in AD brain correlates with reduced expression of Hedgehog target genes involved in neuroprotection (BCL2, MYCN) and neurogenesis. Amyloid-β oligomers disrupt primary cilium integrity, impairing the cilium-dependent trafficking of GLI3 and biasing processing toward the repressor form. This creates a feed-forward loop where reduced Hedgehog signaling diminishes the neuroprotective and neurogenic capacity of neural progenitors.
GLI3 contributes to ventral midbrain patterning through its repressor function, establishing the boundary of the dopaminergic progenitor domain. In PD, the GLI3R/GLI3A balance is disrupted in surviving substantia nigra neurons. Conditional GLI3 overexpression (constitutive repressor form) in mouse dopaminergic neurons accelerates MPTP-induced neurodegeneration by suppressing SHH-dependent survival signaling.
GLI3 loss-of-function in mouse models (extra-toes mutant, Gli3Xt/Xt) causes severe cortical dysgenesis with macrocephaly, heterotopias, and dorsal-ventral patterning defects. These mice exhibit expanded ventral telencephalic identity at the expense of dorsal (cortical) identity, reflecting the loss of GLI3R-mediated dorsal gene activation and ventral gene repression.
| Variant | Type | Clinical Significance |
|---|---|---|
| c.2120_2121insT | Frameshift | Pallister-Hall syndrome (pathogenic) |
| c.2347C>T (p.Gln783Ter) | Nonsense | Pallister-Hall syndrome (pathogenic) |
| c.3529delC | Frameshift | Greig cephalopolysyndactyly (pathogenic) |
| Whole gene deletion | CNV | GCPS with intellectual disability (pathogenic) |
| rs35364414 | Intronic SNP | GWAS association with cortical surface area |