GLI3

This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B.

GLI family zinc finger 3

Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.

Anterior/posterior pattern specification Source: Ensembl
Anterior semicircular canal development Source: Ensembl
Artery development Source: Ensembl
Axon guidance Source: Ensembl
Branching involved in ureteric bud morphogenesis Source: Ensembl
Camera-type eye morphogenesis Source: Ensembl
Cell differentiation involved in kidney development Source: Ensembl
Developmental growth Source: Ensembl
Embryonic digestive tract development Source: BHF-UCL
Embryonic digestive tract morphogenesis Source: Ensembl
Embryonic digit morphogenesis Source: BHF-UCL
Embryonic neurocranium morphogenesis Source: Ensembl
Forebrain dorsal/ventral pattern formation Source: Ensembl
Forebrain radial glial cell differentiation Source: Ensembl
Frontal suture morphogenesis Source: Ensembl
Heart development Source: Ensembl
Hindgut morphogenesis Source: Ensembl
Hippocampus development Source: Ensembl
In utero embryonic development Source: Ensembl
Lambdoid suture morphogenesis Source: Ensembl
Larynx morphogenesis Source: Ensembl
Lateral ganglionic eminence cell proliferation Source: Ensembl
Lateral semicircular canal development Source: Ensembl
Layer formation in cerebral cortex Source: Ensembl
Limb morphogenesis Source: UniProtKB
liver regeneration Source: Ensembl
Lung development Source: Ensembl
Mammary gland specification Source: Ensembl
Melanocyte differentiation Source: Ensembl
Metanephros development Source: Ensembl
Negative regulation of alpha-beta T cell differentiation Source: BHF-UCL
Negative regulation of apoptotic process Source: Ensembl
Negative regulation of canonical Wnt signaling pathway Source: UniProtKB
Negative regulation of cell population proliferation Source: Ensembl
Negative regulation of neuron differentiation Source: Ensembl
Negative regulation of smoothened signaling pathway Source: BHF-UCL
Negative regulation of transcription, DNA-templated Source: UniProtKB
Negative regulation of transcription by RNA polymerase II Source: UniProtKB
Negative thymic T cell selection Source: BHF-UCL
Nose morphogenesis Source: BHF-UCL
Odontogenesis of dentin-containing tooth Source: Ensembl
Oligodendrocyte differentiation Source: Ensembl
Optic nerve morphogenesis Source: Ensembl
Positive regulation of alpha-beta T cell differentiation Source: BHF-UCL
Positive regulation of chondrocyte differentiation Source: Ensembl
Positive regulation of neuroblast proliferation Source: Ensembl
Positive regulation of osteoblast differentiation Source: Ensembl
Positive regulation of protein import into nucleus Source: Ensembl
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Prostate gland development Source: Ensembl
Protein processing Source: Ensembl
Proximal/distal pattern formation Source: Ensembl
Regulation of bone development Source: Ensembl
Regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning Source: Ensembl
Regulation of transcription by RNA polymerase II Source: GO_Central
Response to estrogen Source: Ensembl
Roof of mouth development Source: Ensembl
Sagittal suture morphogenesis Source: Ensembl
Smoothened signaling pathway Source: FlyBase
Smoothened signaling pathway involved in dorsal/ventral neural tube patterning Source: Ensembl
Smoothened signaling pathway involved in spinal cord motor neuron cell fate specification Source: Ensembl
Smoothened signaling pathway involved in ventral spinal cord interneuron specification Source: Ensembl
T cell differentiation in thymus Source: BHF-UCL
Thymocyte apoptotic process Source: BHF-UCL
Tongue development Source: Ensembl
Vocalization behavior Source: Ensembl
Wound healing Source: Ensembl

Nucleus; Cytoplasm; Cilium. GLI3FL is localized predominantly in the cytoplasm while GLI3R resides mainly in the nucleus. Ciliary accumulation requires the presence of KIF7 and SMO. Translocation to the nucleus is promoted by interaction with ZIC1.

Greig cephalo-poly-syndactyly syndrome (GCPS):
Autosomal dominant disorder affecting limb and craniofacial development. It is characterized by pre- and postaxial polydactyly, syndactyly of fingers and toes, macrocephaly and hypertelorism.
Pallister-Hall syndrome (PHS):
An autosomal dominant disorder characterized by a wide range of clinical manifestations. Clinical features include hypothalamic hamartoma, pituitary dysfunction, central or postaxial polydactyly, and syndactyly. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia.
Polydactyly, postaxial A1 (PAPA1):
A condition characterized by the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type A, the extra digit is well-formed and articulates with the fifth or a sixth metacarpal/metatarsal.
Polydactyly, postaxial B (PAPB):
A condition characterized by an extra digit in the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type B the extra digit is not well formed and is frequently in the form of a skin.
Polydactyly, preaxial 4 (PPD4):
A form of polydactyly, a condition defined by the occurrence of supernumerary digits in the upper and/or lower extremities. Preaxial or radial polydactyly refers to the presence of extra digits on the radial side of the hand. PPD4 is an autosomal dominant form characterized by mild duplication of the thumb, syndactyly of various degrees affects fingers 3 and 4, duplication of part or all of the first or second toes and variable toes syndactyly. Some patients have only foot involvement.

Phosphorylated on multiple sites by protein kinase A (PKA) and phosphorylation by PKA primes further phosphorylation by CK1 and GSK3. Phosphorylated by DYRK2 (in vitro). Phosphorylation is essential for its proteolytic processing.
Transcriptional repressor GLI3R, a C-terminally truncated form, is generated from the full-length GLI3 protein (GLI3FL/GLI3-190) through proteolytic processing. This process requires PKA-primed phosphorylation of GLI3, ubiquitination of GLI3 and the presence of BTRC. GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. GLI3R formation leads to its dissociation from SUFU, allowing it to translocate into the nucleus, and repress Hh target genes. When Hh signaling is initiated, SUFU dissociates from GLI3FL and this has two consequences. First, GLI3R production is halted. Second, free GLI3FL translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Phosphorylated in vitro by ULK3.