Disease relevance of Gli3

• A reduction of 50% in the gene dosage of Gli3 in a Gli2-/- background resulted in oesophageal atresia with tracheo-oesophageal fistula and a severe lung phenotype [1].
• Gli2 mutants were found to have abnormal development of maxillary incisors, probably resulting from a mild holoprosencephaly, whereas Gli3 mutants had no major tooth abnormalities [2].
• Glioblastoma 3 (Gli3) is a transcription factor involved in patterning and oncogenesis [3].
• To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied [4].
• The mouse mutant Polydactyly Nagoya (Pdn) defines a novel allele of the zinc finger gene Gli3 [5].

High impact information on Gli3

• Finally, by fate mapping Shh-responding cells in Gli2 and Gli3 mutant limbs, we demonstrate that a specific level of positive Hh signaling is not required to specify digit identities [6].
• Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus [1].
• The Xt heterozygotes show craniofacial defects and a polydactyly phenotype similar to GCPS [7].
• Gli3 (the gene implicated in human Greig cephalopolysyndactyly syndrome) is proposed to negatively regulate Shh by restricting its expression and influence to the posterior mesoderm [8].
• However, whereas these cell identities are restored in Gli3/Smo compound mutants, correct stratification of the rescued ventral cell types is lost [9].

Chemical compound and disease context of Gli3

• Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice [4].
• Genetic susceptibility in the neural tube defects induced by ochratoxin A in the genetic arhinencephaly mouse, Pdn/Pdn [10].
• Pdn/+ female mice, mated with Pdn/+ males, were treated with 40 mg/kg body weight of all-trans-retinoic acid (RA) intraperitoneally on day 10 or 11 of gestation, and effects on the limb development were investigated [11].

Biological context of Gli3

• Gli3 is required for Emx gene expression during dorsal telencephalon development [12].
• However, its importance for lung development is shown by the finding that Gli3XtJ embryos, homozygous for a mutation involving a deletion of the Gli3 gene, have a stereotypic pattern of abnormalities in lung morphogenesis [13].
• In Shh(-/-) or cyclopamine-treated wild-type (WT) lung, we found that Gli3R level is elevated, and this upregulation appears to contribute to defects in proliferation and differentiation observed in the Shh(-/-) mesenchyme, where Gli3 is normally expressed [14].
• Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis [14].
• These results demonstrate that Gli2 and Gli3 share common regulatory mechanisms and modulate Hedgehog target gene expression directly and independently while also regulating Gli1 expression, which in specific contexts, coordinately contributes to target gene activation [15].

Anatomical context of Gli3

• Here, we report on forebrain development in the extra toes (Xt(J)) mouse mutant which carries a null mutation of the Gli3 gene [12].
• However, expression of Shh, which is negatively regulated by Gli3 in the spinal cord, is not affected in the Xt(J)/Xt(J) forebrain [12].
• Together, our data demonstrate both positive and negative regulatory functions for Gli2 and Gli3 in the control of Myf5 activation in the epaxial muscle progenitor cells and in dorsoventral and mediolateral patterning of the somite [16].
• Gli2 and Gli3 have redundant and context-dependent function in skeletal muscle formation [16].
• By contrast, Gli2 is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and Gli3 is broadly expressed along the anteroposterior axis [17].

Associations of Gli3 with chemical compounds

• The chick Su(fu) protein can physically interact with factors known to function in Hh signal transduction including the Drosophila serine/threonine kinase, Fused, and the vertebrate transcriptional regulators Gli1 and Gli3 [18].
• We demonstrate that telencephalic cells from embryonic Gli3Xt/Xt embryos survive better and are more resistant to death induced by cytosine arabinoside, a nucleoside analogue that induces death in neuronal progenitors and neurons, than are control counterparts in vitro [19].
• In contrast, no difference was observed in the tyrosine hydroxylase positive fibers between Pdn/Pdn and +/+ grafts [20].
• In addition, high-performance liquid-chromatography (HPLC) measurements of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) of homozygote (Pdn/Pdn) mouse were examined, and the results were compared with those of other genotypes; heterozygote (Pdn/+) and wild type (+/+) mice [21].
• The arrest of luteinizing hormone-releasing hormone neuronal migration in the genetic arhinencephalic mouse embryo (Pdn/Pdn) [22].

Regulatory relationships of Gli3

• Analysis of Gli3 protein suggests that Rab23 also has a role in promoting the production of Gli3 repressor [23].
• Furthermore, a Ski mutation enhanced the digit abnormalities caused by the Gli3 gene mutation [24].
• Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development [25].
• Zic1 regulates the patterning of vertebral arches in cooperation with Gli3 [26].
• Glial fibrillary acidic protein (GFAP)-expressing glial cells are detected in the prospective cerebral cortex of Xt/Xt animals, indicating that differentiation to glial cells is not disturbed [27].

Other interactions of Gli3

• Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction [28].
• A similar regulatory mechanism involving the N-terminal region was also found for Gli3, but not for Gli1 [29].
• Expression of Gli3 and Hand2 in the mutant limb indicates that the limb prepattern is abnormal [30].
• The present study shows that establishment and positioning of the polarising region is regulated both by restriction of Shh through Gli3 and its positive feedback regulation through formin [31].
• In Hx mice we found a down-regulation of Gli3 in the anterior region of the limb bud [32].

Analytical, diagnostic and therapeutic context of Gli3

• Previous studies suggested that the Gli3 zinc finger transcription factor is an important signal transducer of Shh signaling during animal development [33].
• Shh pathway inhibition was monitored by semiquantitative reverse transcriptase-polymerase chain reaction for expression of epididymal Gli1 and Gli3 [34].
• All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3 [35].
• Now we can discriminate +/+, Pdn/+, Pdn/Pdn embryos from the PCR products [36].
• Cloning and sequence analysis of the murine Gli3 cDNA [37].

References