Disease relevance of Gli2

• 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 [1].
• Interestingly, Gli2 levels were elevated in medulloblastoma cells but not in normal granule neuron precursors during cerebellar development in mice lacking Gli1 [2].
• When grown as a subcapsular graft, the Gli2(-/-) UGS exhibited prostatic differentiation but also displayed areas of focal epithelial hyperplasia [3].
• 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 [4].
• We report here that mutant mice lacking Gli2 function exhibit foregut defects, including stenosis of the oesophagus and trachea, as well as hypoplasia and lobulation defects of the lung [4].

High impact information on Gli2

• Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors [5].
• Basal cell carcinomas in mice overexpressing Gli2 in skin [6].
• Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus [4].
• These observations indicate that Shh-dependent Gli2 activator function in the epidermis is essential for hair follicle development [7].
• By transgenic rescue experiments, we show that epidermal Gli2 function alone is sufficient to restore hair follicle development in Gli2(-/-) skin [7].

Biological context of Gli2

• Although the Gli1, Gli2, and Gli3 zinc finger proteins are known to be effectors of Hh signaling in vertebrates, the mechanisms regulating activity of these transcription factors remain poorly understood [3] [4] [8].
• 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 [9].
• We have found that the floor plate throughout the midbrain, hindbrain and spinal cord does not form in Gli2 homozygotes [10].
• To further define their roles in regulating myogenesis, the function of wild type and dominant-negative forms of Gli2 and Meox1 were examined in the context of differentiating P19 stem cells [11].
• The Ptc1(-/-) phenotype is rescued, with restoration of dorsal cell types, by the lack of Gli2, but only in the caudal neural tube [12].

Anatomical context of Gli2

• In cultured fibroblasts, Gli1 was more potent than Gli2 at inducing cell transformation [2].
• The family consists of Gli(1), Gli2, and Gli3, all of which are expressed in the developing mouse limb bud [13].
• Interestingly, Gli2 and Gli3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241-246) mutant mice exhibit different subsets of skeletal defects indicating that they implement specific functions in the development of the neural crest, somite and lateral plate mesoderm derivatives [14].
• Gli2 mutants fail to develop a floor plate yet still develop motor neurons, which occupy the ventral midline of the neural tube [15].
• In cultured cells, truncation of the activation domain in the C-terminal half results in a protein with repressor activity, while removal of the repression domain at the N terminus converts Gli2 into a strong activator [16].

Associations of Gli2 with chemical compounds

• The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3 [17].
• These results underscore the qualitative difference in oncogenicity of GLI1 and Gli2 when overexpressed in skin, and reveal a previously unanticipated role for the Gli2 NH(2) terminus in defining tumor phenotype [18].

Regulatory relationships of Gli2

• 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 [19].
• Luciferase assay showed that the 3.6-kb Fgf15 enhancer/promoter was activated by Gli2 [20].

Other interactions of Gli2

• In addition, specific components in the Hedgehog pathway are either ectopically activated (Ptc, Ptc-2, Gli1) or repressed (Gli2) [21].
• The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants [1].
• 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 [22].
• Taken together, these results support the existence of a regulatory loop between Gli2, Meox1, and Pax3 that is essential for specification of mesodermal cells into the muscle lineage [11].
• The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling [23].

Analytical, diagnostic and therapeutic context of Gli2

• Although Gli2 principally mediates the activator function of Shh, surprisingly we observed minimal changes in glandular development in the Gli2 mutant stomach [24].
• Promoter analyses, including chromatin immunoprecipitation and electrophoretic mobility shift assays, provided direct evidence that Gli2 physically interacts with the BMP-2 promoter [23].
• In this study, we investigated the role of Gli2 signal transducer in Shh induction of oligodendrocytes by studying oligodendrocyte development in Gli2-null mutants [25].
• RESULTS: By reverse transcriptase-polymerase chain reaction, a unique difference between the fistula tract and control tissues was that Gli-2 (downstream signaling molecule of Shh) messenger RNA levels were much lower in the fistula tract than in the adjacent esophagus (P =.002) [26].

References