GLI3
<div class="infobox infobox-gene">
<h3>GLI3 (GLI Family Zinc Finger 3)</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>GLI Family Zinc Finger 3</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>GLI3</td></tr> [@johnston2005]
<tr><td><strong>Chromosomal Location</strong></td><td>7p14.1</td></tr> [@petrova2014]
<tr><td><strong>NCBI Gene ID</strong></td><td>[2737](https://www.ncbi.nlm.nih.gov/gene/2737)</td></tr> [@theil1999]
<tr><td><strong>OMIM</strong></td><td>[165240](https://omim.org/entry/165240)</td></tr> [@litingtung2000]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000106571](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000106571)</td></tr> [@hasenpuschtheil2018]
<tr><td><strong>UniProt (Protein)</strong></td><td>[P10071 (GLI3)](https://www.uniprot.org/uniprot/P10071)</td></tr> [@niewiadomski2014]
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), Greig Cephalopolysyndactyly, Pallister-Hall Syndrome, [Parkinson's Disease](/diseases/parkinsons-disease), Acrocallosal Syndrome</td></tr>
</table>
</div>
Overview
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](/mechanisms/hedgehog-pathway). While [GLI1](/genes/gli1) acts solely as an activator and [GLI2](/genes/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.
Gene Structure and Expression
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](/brain-regions/cortex), where GLI3 regulates progenitor proliferation, cortical size, and dorsal-ventral specification. In the adult brain, GLI3 is expressed in the cortex, [hippocampus](/brain-regions/hippocampus), [astrocytes](/cell-types/astrocytes), and adult neural stem cells of the SVZ. The [Allen Brain Atlas](https://human.brain-map.org/) shows widespread cortical expression with enrichment in frontal and parietal regions.
Protein Function and Mechanism
GLI3 is a bifunctional transcription factor with an architecture similar to [GLI2](/genes/gli2):
- N-terminal repressor domain (aa 1-397): Contains a highly efficient repressor domain that recruits [HDAC](/entities/hdac-enzymes) complexes; this domain is retained in the processed GLI3R form
- Zinc finger DNA-binding domain (aa 480-632): Five C2H2 zinc fingers recognizing the consensus GLI-binding site 5'-GACCACCCA-3'
- Processing determinant domain (PDD): Region C-terminal to the zinc fingers that is critical for proteasomal processing
- C-terminal activation domain (aa 1100-1580): Transactivation domain present only in full-length GLI3A
The processing of GLI3 is the central regulatory event:
In the absence of Hedgehog signal, [SUFU](/genes/sufu) binds GLI3 and promotes its sequential phosphorylation by PKA (Ser849, Ser865, Ser877), GSK3β, and CK1α
Phosphorylated GLI3 is recognized by the β-TrCP/SCF E3 ubiquitin ligase, which ubiquitinates the C-terminal region
The proteasome processes GLI3 into a stable 83 kDa N-terminal fragment (GLI3R) containing the repressor and DNA-binding domains but lacking the activation domain
GLI3R translocates to the nucleus and represses Hedgehog target genesUpon pathway activation by [SHH](/genes/shh) binding to [PTCH1](/genes/ptch1) and [SMO](/genes/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.
Disease Associations
Neurodevelopmental Disorders
GLI3 mutations cause several neurodevelopmental syndromes:
- Greig Cephalopolysyndactyly Syndrome (GCPS, OMIM 175700): Caused by haploinsufficiency or deletions encompassing GLI3. Features include macrocephaly, frontal bossing, hypertelorism, and polysyndactyly. Large deletions may include contiguous genes causing intellectual disability. Corpus callosum agenesis and hydrocephalus occur in severe cases.
- Pallister-Hall Syndrome (PHS, OMIM 146510): Caused by truncating mutations in the middle third of GLI3 that produce a constitutive repressor. Features include hypothalamic hamartoma, bifid epiglottis, imperforate anus, and polydactyly. Hypothalamic hamartomas can cause gelastic seizures and precocious puberty.
- Acrocallosal Syndrome (ACLS): Overlaps with GCPS; features corpus callosum agenesis and intellectual disability.
Alzheimer's Disease
In [AD](/diseases/alzheimers-disease), 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.
Parkinson's Disease
GLI3 contributes to ventral midbrain patterning through its repressor function, establishing the boundary of the dopaminergic progenitor domain. In [PD](/diseases/parkinsons-disease), the GLI3R/GLI3A balance is disrupted in surviving substantia nigra [neurons](/entities/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.
Common Variants
| 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 |
Therapeutic Implications
- SMO agonists (SAG, purmorphamine): Shift GLI3 processing from repressor to activator; potential neuroprotective strategy in AD/PD
- Proteasome inhibitors: Block GLI3 processing to GLI3R; research tool for studying GLI3A-dependent transcription
- GSK3β inhibitors (lithium, CHIR99021): Reduce GLI3 phosphorylation and processing, increasing GLI3A:GLI3R ratio; lithium's neuroprotective effects may partly operate through this mechanism
- PKA inhibitors: Prevent initiating phosphorylation required for GLI3 processing
- Gene therapy approaches: AAV-mediated modulation of GLI3A:GLI3R ratio in neural progenitors for neurodegenerative disease
See Also
- [GLI1](/genes/gli1) — Hedgehog pathway transcriptional activator
- [GLI2](/genes/gli2) — Primary Hedgehog pathway activator (bifunctional)
- [SUFU](/genes/sufu) — Suppressor of Fused, key negative regulator of GLI3 processing
- [SMO](/genes/smo) — Smoothened receptor, upstream pathway component
- [PTCH1](/genes/ptch1) — Patched1 receptor
- [SHH](/genes/shh) — Sonic Hedgehog ligand
External Links
- [NCBI Gene: GLI3](https://www.ncbi.nlm.nih.gov/gene/2737)
- [UniProt: P10071](https://www.uniprot.org/uniprot/P10071)
- [OMIM: 165240](https://omim.org/entry/165240)
- [GeneCards: GLI3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=GLI3)
- [Allen Brain Atlas: GLI3](https://human.brain-map.org/)
- [ClinVar: GLI3](https://www.ncbi.nlm.nih.gov/clinvar/?term=GLI3)
References
[Unknown, Biesecker LG, The Greig cephalopolysyndactyly syndrome (2008) (2008)](https://doi.org/10.1186/1750-1172-3-10)
[Wang B et al., Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb (2000) (2000)](https://doi.org/10.1016/S0092-8674(00)
[Bai CB et al., All mouse ventral spinal cord patterning by hedgehog is Gli dependent (2004) (2004)](https://doi.org/10.1016/j.devcel.2004.02.001)
[Tole S et al., Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes (2000) (2000)](https://doi.org/10.1006/dbio.2000.9765)
[Johnston JJ et al., Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes (2005) (2005)](https://doi.org/10.1086/432266)
[Unknown, Petrova R & Bhatt R, Hedgehog-Gli pathway in brain development and disease (2014) (2014)](https://doi.org/10.1016/j.neulet.2014.04.033)
[Theil T et al., Gli3 is required for Emx gene expression during dorsal telencephalon development (1999) (1999)](https://doi.org/10.1242/dev.126.16.3561)
[Unknown, Litingtung Y & Chiang C, Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3 (2000) (2000)](https://doi.org/10.1038/35005072)
[Hasenpusch-Theil K et al., Gli3 controls the onset of cortical neurogenesis by regulating the radial glial cell cycle (2018) (2018)](https://doi.org/10.1242/dev.163553)
[Niewiadomski P et al., Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling (2014) (2014)](https://doi.org/10.1016/j.celrep.2013.12.003)