Disease relevance of Gli

• Amplification of the gli gene in childhood sarcomas [1].
• 3. A 15-fold level of gli amplification and gli mRNA transcripts were also detected in an established cell line from a patient with a rare form of osteosarcoma characterized by multipotential histological features [1].
• The tumor with gli gene amplification lacked the usual histological features of alveolar or embryonal rhabdomyosarcoma; however, ultrastructural analysis of tumor cells established in culture revealed attenuated sarcomeres, resembling those found in primitive rhabdomyoblasts [1].
• In one of the 13 rhabdomyosarcomas studied, genomic DNA restriction fragments containing the gli gene were amplified approximately 30-fold, and expression of the 4.0-kilobase gli mRNA transcript was identified [1].
• The gli gene, originally identified by its amplified copy number in cells from a human malignant glioma, has a predicted translation product that contains five tandem DNA-binding zinc finger motifs related to those of Krüppel, a developmentally important Drosophila segmentation gene [1].

High impact information on Gli

• The Gli homolog Cubitus interruptus (Ci) is involved in controlling the transcription of Hh target genes [2].
• Gliotactin, a novel transmembrane protein on peripheral glia, is required to form the blood-nerve barrier in Drosophila [3].
• Gli/Zic factors pattern the neural plate by defining domains of cell differentiation [4].
• Conversely, Gli proteins are widely expressed, induce neurogenesis and inhibit neural crest differentiation [4].
• One such gene, gleeful, related to the vertebrate Gli genes, is essential for somatic muscle development and sufficient to cause neural cells to express a muscle marker [5].

Biological context of Gli

• Members of the Hedgehog (HH) family of secreted signaling molecules specify cell fate during animal development by controlling the activity of members of the Gli family of zinc-finger transcription factors in responding cells [6].
• Within a minimal disc enhancer, we identify the DNA sequences that are necessary and sufficient for the control by Ci, show that the same sequences respond to the activator and repressor forms of Ci, and demonstrate that their activities can be replaced by a single synthetic Gli-binding site [7].
• To address this hypothesis, we analyzed Gli expression and the Gli mutant phenotype in Drosophila epithelia [8].
• Hedgehog signaling regulates transcription through Gli/Ci binding sites in the wingless enhancer [9].
• Here, we describe the molecular genetic analysis of gliotactin, a novel transmembrane protein that is transiently expressed on peripheral glia and that is required for the formation of the peripheral blood-nerve barrier [3].

Anatomical context of Gli

• Gliotactin (Gli) is a cholinesterase-like molecule that is necessary for blood-nerve barrier integrity, and may, therefore, contribute to SJ development or function [8].
• Prior to prehair extension, Gli and Cora were restricted to basolateral membranes [10].
• Tissue expression of gli during gestation was demonstrated in Meckel's precartilage mesenchyme, the basis occipitus, rib mesenchymal condensations, primordial vertebral bodies, digital mesenchymal condensations in forefoot and hindfoot plates, the ependymal layer of the spinal cord, and the mesoderm of the gastrointestinal tract [11].
• Cytogenetic analysis of this cell line disclosed double-minute chromatin bodies, with no apparent rearrangements in the region of the gli locus on the long arm of chromosome 12, bands q13 to q14 [1].
• Gliotactin and Discs large form a protein complex at the tricellular junction of polarized epithelial cells in Drosophila [12].

Physical interactions of Gli

• Surprisingly, Gliotactin localization at the TCJ was independent of its PDZ-binding motif and Gliotactin did not bind directly to Discs large [12].

Regulatory relationships of Gli

• The cubitus interruptus (ci) gene of Drosophila is expressed in all anterior compartment cells in both embryos and imaginal disks where it encodes a putative zinc-finger protein related to the vertebrate Gli and C. elegans Tra-1 proteins [13].

Other interactions of Gli

• Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus [14].
• The repressor and activator forms of Cubitus interruptus control Hedgehog target genes through common generic gli-binding sites [7].
• In both cases, Hh signaling proceeds through the activation of the seven-transmembrane protein Smoothened (Smo), which is thought to convert the Gli family of transcription factors from transcriptional repressors to transcriptional activators [15].
• Transient apical polarization of Gliotactin and Coracle is required for parallel alignment of wing hairs in Drosophila [10].
• Genetic and cell biological assays demonstrated that Gli and Cora function to align hairs independently of frizzled [10].

Analytical, diagnostic and therapeutic context of Gli

• Amplified gli sequences were cytogenetically localized by in situ hybridization to a homogeneously staining region contained on a derivative chromosome 7 [1].
• A similar level of gli gene amplification was observed in cryopreserved primary tumor cells from this patient, confirming that gene amplification took place during tumor development and not during in vitro cell culture [1].

References