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Key Event Title
Decrease, GLI1/2 target gene expression
|Level of Biological Organization|
Key Event Components
|gene expression||zinc finger protein GLI1||decreased|
|gene expression||zinc finger protein GLI2||decreased|
Key Event Overview
AOPs Including This Key Event
|All life stages|
Key Event Description
The Glioma-associated onocogene (GLI) family of zinc finger transcription factors (Gli1, Gli2, Gli3) are the primarily downstream effectors of the Hedgehog (HH) signaling cascade. When HH ligand binds to Patched (PTCH), its’ inhibition on SMO is relieved. SMO this then able to accumulate to the tip of primary cilium in its’ active form (Corbit, Aanstad et al. 2005, Rohatgi, Milenkovic et al. 2007, Kim, Kato et al. 2009). SMO causes the GLI family to become dislodged from their complex with the negative regulator of HH signaling, Suppressor of Fused (Sufu) (Kogerman, Grimm et al. 1999, Pearse, Collier et al. 1999, Stone, Murone et al. 1999, Tukachinsky, Lopez et al. 2010). The GLI-Sufu complex maintains retention of Gli in the cytosol allowing for exposure to phosphorylation via protein kinase A (PKA) which inhibits downstream signal transduction (Tuson, He et al. 2011). When SMO is activated the GLI2/3-Sufu complex is dismantled allowing for retrograde transport of GLI back into the nucleus (Kim, Kato et al. 2009). Following translocation into the nucleus, the GLI family of transcription factors initiates transcription of a variety of genes. The genes transcribed by activation of the SHH pathway are cell type dependent but commonly include GLI1 and PTCH1 (Stamataki, Ulloa et al. 2005, Cohen, Kicheva et al. 2015, Tickle and Towers 2017). During development of the neural tube SHH is associated with NKX6.1, OLIG2, NKX2.2 and the FOXA2 genes (Vokes, Ji et al. 2007, Kutejova, Sasai et al. 2016). Other genes have are known targets of GLI transcription include PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLA, FOXF1, FOXFL1, PRDM1, JAG2, GREM1, FOXB2, FOXA2, FOXB2, FOXC1, FOXC2, FOXD1, FOXE1, FOXF1, FOXF2, FOXL1 and follistatin (Katoh and Katoh 2009, Everson, Fink et al. 2017).
How It Is Measured or Detected
- Changes in gene expression can be measured using serial analysis of gene expression (SAGE), rapid analysis of gene expression (RAGE), RT-PCR, Northern/Southern blotting, differential display, and DNA microarray assay.
Domain of Applicability
- Sex- The GLI family of transcription factors is present in both male and females and differences in gene expression has not been demonstrated.
- Life stages- The Hedgehog pathway is a major pathway in embryonic development. Aberrant activation of HH signalling is known to cause cancer (Dahmane, Lee et al. 1997, Kimura, Stephen et al. 2005). For these reasons all stages of life are of relevance.
- Taxonomic-HH signalling including the GLI transcription factors is present in vertebrates and some invertebrates including flies (Denef, Neubüser et al. 2000, Huangfu and Anderson 2005)
Cohen, M., A. Kicheva, A. Ribeiro, R. Blassberg, K. M. Page, C. P. Barnes and J. Briscoe (2015). "Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms." Nature Communications 6(1): 6709.
Corbit, K. C., P. Aanstad, V. Singla, A. R. Norman, D. Y. R. Stainier and J. F. Reiter (2005). "Vertebrate Smoothened functions at the primary cilium." Nature 437(7061): 1018-1021.
Dahmane, N., J. Lee, P. Robins, P. Heller and A. Ruiz i Altaba (1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours." Nature 389(6653): 876-881.
Denef, N., D. Neubüser, L. Perez and S. M. Cohen (2000). "Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened." Cell 102(4): 521-531.
Everson, J. L., D. M. Fink, J. W. Yoon, E. J. Leslie, H. W. Kietzman, L. J. Ansen-Wilson, H. M. Chung, D. O. Walterhouse, M. L. Marazita and R. J. Lipinski (2017). "Sonic hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis." Development 144(11): 2082-2091.
Huangfu, D. and K. V. Anderson (2005). "Cilia and Hedgehog responsiveness in the mouse." Proc Natl Acad Sci U S A 102(32): 11325-11330.
Katoh, Y. and M. Katoh (2009). "Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation." Curr Mol Med 9(7): 873-886.
Kim, J., M. Kato and P. A. Beachy (2009). "Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus." Proc Natl Acad Sci U S A 106(51): 21666-21671.
Kimura, H., D. Stephen, A. Joyner and T. Curran (2005). "Gli1 is important for medulloblastoma formation in Ptc1+/- mice." Oncogene 24(25): 4026-4036.
Kogerman, P., T. Grimm, L. Kogerman, D. Krause, A. B. Undén, B. Sandstedt, R. Toftgård and P. G. Zaphiropoulos (1999). "Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1." Nat Cell Biol 1(5): 312-319.
Kutejova, E., N. Sasai, A. Shah, M. Gouti and J. Briscoe (2016). "Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs." Dev Cell 36(6): 639-653.
Pearse, R. V., 2nd, L. S. Collier, M. P. Scott and C. J. Tabin (1999). "Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators." Dev Biol 212(2): 323-336.
Rohatgi, R., L. Milenkovic and M. P. Scott (2007). "Patched1 regulates hedgehog signaling at the primary cilium." Science 317(5836): 372-376.
Stamataki, D., F. Ulloa, S. V. Tsoni, A. Mynett and J. Briscoe (2005). "A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube." Genes Dev 19(5): 626-641.
Stone, D. M., M. Murone, S. Luoh, W. Ye, M. P. Armanini, A. Gurney, H. Phillips, J. Brush, A. Goddard, F. J. de Sauvage and A. Rosenthal (1999). "Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli." J Cell Sci 112 ( Pt 23): 4437-4448.
Tickle, C. and M. Towers (2017). "Sonic Hedgehog Signaling in Limb Development." Front Cell Dev Biol 5: 14.
Tukachinsky, H., L. V. Lopez and A. Salic (2010). "A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes." J Cell Biol 191(2): 415-428.
Tuson, M., M. He and K. V. Anderson (2011). "Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube." Development 138(22): 4921-4930.
Vokes, S. A., H. Ji, S. McCuine, T. Tenzen, S. Giles, S. Zhong, W. J. Longabaugh, E. H. Davidson, W. H. Wong and A. P. McMahon (2007). "Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning." Development 134(10): 1977-1989.