+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways



Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways



Plos Medicine 5(12): E239



Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis. Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model. HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 051523040

Download citation: RISBibTeXText

PMID: 19071955


Related references

A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients. Clinical Cancer Research 20(6): 1687-1697, 2014

Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. International Journal of Oncology 35(1): 187-192, 2009

Hedgehog signalling in T-cell development: a non-redundant role for Gli1. Cell Cycle 9(22): 4428, 2010

Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch- dependent ubiquitination. Nature Cell Biology 8(12): 1415, 2006

Activation of the transcription factor Gli1 and the sonic hedgehog signalling pathway in skin tumours. Nature (London) 389(6653): 876-881, 1997

Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391(6666): 493-496, 1998

Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells. Journal of Pathology 225(4): 525-534, 2011

SHP (small heterodimer partner) suppresses the transcriptional activity and nuclear localization of Hedgehog signalling protein Gli1. Biochemical Journal 427(3): 413-422, 2010

Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proceedings of the National Academy of Sciences of the United States of America 104(14): 5895-5900, 2007

Antagonistic cross-regulation between Wnt and Hedgehog signalling pathways controls post-embryonic retinal proliferation. Development 139(19): 3499-3509, 2012

Genetic analysis of converging hedgehog and wingless signalling pathways in the Drosophila embryo. Journal of Cellular Biochemistry Suppl. 0(18B): 236, 1994

Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. Plos one 8(6): E65403, 2013

Noncanonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma. Molecular Cancer Research 11(6): 604-615, 2013

Dynamic Hedgehog signalling pathway activity in germline stem cells. Andrology 2(2): 267-274, 2014