Disease relevance of Gli1

• Therefore, Gli1 is not only a marker of pathway activation but also plays a functional role in medulloblastoma formation [1].
• We show that at these stages in the murine mandibular arch in the absence of epithelium, the Shh targets Ptc1 and Gli1 are upregulated in diastema mesenchyme, an edentulous region between the sites of molar and incisor tooth formation [2].
• In human gastric cancer cells, inhibition of Hh signaling reduces the level of sFRP-1 transcript, whereas ectopic expression of Gli1 increases the level of sFRP-1 transcript [3].
• Development of basal cell carcinomas (BCCs) in skin is associated with uncontrolled Sonic hedgehog (Shh) signaling, which operates primarily through the Gli family of transcription factors [4].
• Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation [5].

High impact information on Gli1

• Here we show that ectopic expression of the zinc-finger transcription factor Gli1 in the embryonic frog epidermis results in the development of tumours that express endogenous Gli1 [6].
• Two Shh target genes, ptc itself and Gli, were derepressed in the ectoderm and mesoderm but not in the endoderm [7].
• Thus, Shh-N signaling may result in dephosphorylation of a target factor that is required for activation of COUP-TFII-, Islet1-, and Gli response element-dependent gene expression [8].
• Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation [9].
• MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription [10].

Chemical compound and disease context of Gli1

• 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 [11].

Biological context of Gli1

• Homozygous ptc1 cells expressed high levels of ptc1-lacZ without Hh stimulation. ptc1-lacZ expression was dependent on cell density in ptc1 homozygotes and Hh-stimulated heterozygotes but was independent of density when Gli1 was used to activate ptc1-lacZ [12].
• Additionally, overexpression of Gli1 induced target gene expression in Gli2(-/-)3(-/-) MEFs, while Shh stimulation did not [13].
• 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 [13].
• Cyclopamine treatment reduced Gli1 expression by 61% and initiation of cauda sperm motility by 50% [14].
• Although genetic epistasis experiments place IFT proteins downstream of the Hh receptor and upstream of the Gli transcription factors, the mechanism by which IFT regulates Gli function is unknown [15].

Anatomical context of Gli1

• Ectopic application of Shh protein to mandibular mesenchyme induced the expression of Ptc and Gli1 [16].
• Furthermore, expression of both copies of Gli1 in place of Gli2 does not disrupt spinal cord patterning, but does result in new gain-of-function defects that lead to lethality [17].
• In frog embryos, Gli1 is expressed transiently in the prospective floor plate during gastrulation and in cells lateral to the midline during late gastrula and neurula stages [18].
• Gli1 was localized primarily to the nucleus of both HeLa cells and the Shh-responsive cell line MNS-70; co-expression with mSu(fu) resulted in a striking increase in cytoplasmic Gli1 immunostaining [19].
• In cultured fibroblasts, Gli1 was more potent than Gli2 at inducing cell transformation [1].

Associations of Gli1 with chemical compounds

• Nuclear localization of Gli1 was increased in Shh-treated IBE cells, which was not affected by LY294002 [20].
• Adriamycin disruption of the Shh-Gli pathway is associated with abnormalities of foregut development [21].

Physical interactions of Gli1

• Different domains of Smo are involved in Ptc binding and activation of a Gli reporter construct [22].
• A Gli-binding site located within the ES enhancer is required for enhancer activation by Shh signaling in transfected 3T3 cells and in epaxial somite progenitors in transgenic embryos [23].

Regulatory relationships of Gli1

• Ptc represses expression of Hh target genes such as Gli1 and ptc1 itself [24].
• In both mutants Gli2 expression pattern was not altered, whereas Gli1 expression was anteriorly up-regulated adjacent to the ectopic Shh domain [25].
• At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme [26].
• Our results demonstrate that Gli1 is not required to induce Pdgfra expression during embryonic bone development, and are consistent with previous findings that Pdgfralpha and Hh pathways serve different functions in, e.g., bone, gut, and lung development [27].
• Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins [28].

Other interactions of Gli1

• The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis [29].
• A similar regulatory mechanism involving the N-terminal region was also found for Gli3, but not for Gli1 [30].
• We found that while neither Gli1 nor Gli3 are required for normal prostate ductal budding, the urogenital sinus (UGS) of the Gli2(-/-) mutant mouse displays aberrant ductal budding in utero [31].
• In wild-type E11.0 molar tooth mesenchyme SHH-soaked beads induced the expression of Ptc and Gli1 [32].
• We show here that the expression of Ptc, but not Gli1, was downregulated in the dental mesenchyme of Msx1 mutants [32].

Analytical, diagnostic and therapeutic context of Gli1

• Shh pathway inhibition was monitored by semiquantitative reverse transcriptase-polymerase chain reaction for expression of epididymal Gli1 and Gli3 [14].
• EDL did not alter epididymal segmentation, but Shh, Ptc, and Gli1 expression was significantly altered at specific times after the ligation [33].
• We examined the ocular phenotypes of Shh and Gli combination mutant mouse embryos and monitored proximodistal and dorsoventral patterning by the expression of specific eye development regulatory genes using in situ hybridization [34].
• Results from chromatin immunoprecipitation indicate that Gli1 is involved in transcriptional regulation of sFRP-1 [3].
• We find that zebrafish Gli3 has an early function as an activator of Hh target genes that overlaps with Gli1 activator function in the ventral neural tube [35].

References