GLI Proteins in Human Genetic Disease

Zhulyn Olena, University of Toronto, Toronto, Ontario, Canada
Hui Chi‐chung, University of Toronto, Toronto, Ontario, Canada

Published online: December 2012

DOI: 10.1002/9780470015902.a0024402

GLI1, GLI2 and GLI3 transcription factors are the key effectors of mammalian Hedgehog signalling. Mutations in these transcription factors are implicated in severe congenital malformations and malignancies in humans and in mice. Analysis of mouse models has revealed that the patterning and development of multiple organ systems is dependent on a tightly regulated balance of Gli activator and repressor activity. Consequently, mutations in the Hh pathway machinery that affect Gli function or processing result in phenotypes with a striking resemblance to GLI-associated disorders. The primary cilium was identified as a critical component of Hh signalling due to the phenotypic overlap between Hh-pathway mutants and mice with defects in ciliogenesis. Many mutations in genes regulating cilia structure and function have been identified in human ciliopathies. This new class of diseases shares significant phenotypic overlap with GLI-related syndromes. Phenotypic analysis of mice with compromised cilia function has revealed new aspects of Gli regulation demonstrating the utility of mouse models in the characterisation of novel disease phenotypes.

Key Concepts:

  • Balance of GLI activator and repressor is required for normal development.
  • Shift of the balance towards low or high GLI3R levels results in severe congenital malformations.
  • Shift of the balance towards high GLI activator results in cancer.
  • Mutations affecting different domains of bifunctional transcription factor Gli3 give rise to distinct phenotypes.
  • Mutations affecting Hh pathway machinery affect Gli processing and activity and result in Gli-related phenotypes.
  • The primary cilium is critical for Hh signal transduction.
  • Mutations in regulators of primary cilia structure and function result in ciliopathies, which share many overlapping phenotypes with GLI-associated syndromes.

Keywords: hedgehog signalling; GLI transcription factor; congenital malformations; cancer; ciliopathy; mouse models of disease

Figure 1. Domain architecture and distribution of disease-associated mutations in human GLI transcription factors. GLI2 and GLI3 encode bifunctional transcription factors with conserved repression and transactivation domains. GLI1 acts primarily as an activator (Hui and Angers, 2011). Annotated Pallister–Hall syndrome (PHS) and Greig cephalopolysyndactyly syndrome (GCPS) mutations were described by Johnston et al. (2005, 2010); sub-Greig cephalopolysyndactyly syndrome (sub-GCPS), sub-Pallister–Hall syndrome (sub-PHS) and oral-digital-facial syndrome (OFDS) mutations were described in Johnston et al. (2010). Acrocallosal syndrome (ACLS) mutation was described by Elson et al. (2002). Nonsyndromic preaxial polydacytly type IV and type I (PPDIV and PPDI) were described in Fujioka et al. (2005) and Radhakrishna et al. (1999). Nonsyndromic postaxial polydactyly type A and B (PAPA/B) were described by Radhakrishna et al. (1997a, 1997b, 1999).
Figure 2. Signal transduction in the mammalian Shh pathway. Schematic drawing of the Shh pathway in the presence or absence of the Shh ligand. In the absence of ligand the pathway is ‘OFF’: Ptch1, the Shh receptor, localises to the primary cilium and inhibits Smo. Smo localises to intracellular vesicles. Sufu-Gli complexes traffic into and out of the cilium at a low rate, their movement into the cilia is inhibited by the activity of PKA. Sufu-bound Gli proteins are inactive. Sufu, Kif7 and multiple kinases promote the proteasome dependent cleavage of Gli3 into a truncated Gli3R, which inhibits Shh-target gene transcription (Hui and Angers, 2011; Jiang and Hui, 2008). The pathway is ‘ON’ when the Shh ligand binds to Ptch1, which moves into intracellular vesicles. Derepressed Smo moves into the cilia and promotes the dissociation of Sufu–Gli complexes. Gli leaves the cilium and is activated through an unknown mechanism to upregulate Shh-target genes in the nucleus, which requires functional Kif7 and Sufu.
Figure 3. Dosage of Gli3 activity is critical for normal development as illustrated in the limb. Gli3 patterns the limb in two phases: during limb initiation, Gli3 polarises the limb into an anterior and posterior compartment through mutual antagonism with the transcription factor Hand2. After budding is completed, Shh is induced in the posterior margin of the limb. By inhibiting the cleavage of full-length Gli3 into Gli3R, Shh creates a gradient of Gli activity across the limb with high activator at the posterior and repressor at the anterior. The balance of Gli activity regulates the expansion of limb progenitors and restricts digit number to five digits. Disruption of this balance results in aberrant digit patterning. Delayed ossification and preaxial (red arrow) or central polydactyly (*) is observed in the Gli3699/699 model. Low levels of Gli3R result in thumb duplication (black arrow) in Gli3XtJ/+ and severe polydactyly in Gli3XtJ/XtJ mice. Components labelled are humerus (hu), ulna (ul), radius (ra), digits number 1–5.
Figure 4. The primary cilium is a critical niche for Shh signal transduction. Mutations affecting anterograde IFT affect the cell's ability to establish and maintain primary cilia. The resulting cilium is short and stubby and is associated not only with a failure to activate Shh signalling but also deficient Gli3R processing. In contrast, defects in retrograde transport result in wide and bulbous cilia, and the accumulation of both IFT particles and Shh pathway components, including the Gli proteins, at the ciliary tips. Such defects are associated with elevated Shh signalling and deficient Gli3R processing. Analysis of mouse mutants with mutations in IFT machinery reveals a striking persistence of Gli3R processing defects and phenotypes associated with aberrant Shh signalling as summarised above. Filled circle indicates that the phenotype is present, blank circle indicates the phenotype is absent, ND indicates phenotype presence was not determined.
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 References
    Ali BR, Silhavy JL, Akawi NA, Gleeson JG and Al-Gazali L (2012) A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Orphanet Journal of Rare Diseases 7(1): 27.
    Avila M, Gigot N, Aral B et al. (2011) GLI3 is rarely implicated in OFD syndromes with midline abnormalities. Human Mutation 32(11): 1332–1333.
    Bae G, Domené S, Roessler E et al. (2011) Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. American Journal of Human Genetics 89(2): 231–240.
    Böse J, Grotewold L and Rüther U (2002) Pallister–Hall syndrome phenotype in mice mutant for Gli3. Human Molecular Genetics 11(9): 1129–1135.
    Bowers M, Eng L, Lao Z et al. (2012) Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3. Developmental Biology 370(1): 110–124.
    Buttitta L, Mo R, Hui CC and Fan CM (2003) Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Development 130(25): 6233–6243.
    Chen M, Wilson CW, Li Y et al. (2009) Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes and Development 23(16): 1910–1928.
    Cheung HO, Zhang X, Ribeiro A et al. (2009) The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Science Signaling 2(76): ra29.
    Chih B, Liu P, Chinn Y et al. (2012) A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biology 14(1): 61–72.
    Dafinger C, Liebau MC, Elsayed SM et al. (2011) Brief report mutations in KIF7 link Joubert syndrome with sonic hedgehog signaling and microtubule dynamics. Journal of Clinical Investigation 121(7): 3–8.
    Davis EE and Katsanis N (2012) The ciliopathies: a transitional model into systems biology of human genetic disease. Current Opinion in Genetics and Development 22(3): 290–303.
    Elson E, Perveen R, Donnai D, Wall S and Black GC (2002) De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models. Journal of Medical Genetics 39(11): 804–806.
    Fujioka H, Ariga T, Horiuchi K et al. (2005) Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I. Clinical Genetics 67(5): 429–433.
    Goetz SC and Anderson KV (2010) The primary cilium: a signaling centre during vertebrate development. Nature Reviews Genetics 11(5): 331–344.
    Hall JG, Pallister PD, Clarren SK et al. (1980) Congenital hypothalamic imperforate anus and postaxial polydactyly a new syndrome? Part I/: clinical, causal, and pathogenetic considerations. American Journal of Medical Genetics 7(1): 47–74.
    Hsu SC, Zhang X, Yu C et al. (2011) Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. Development 138(17): 3791–3801.
    Huangfu D and Anderson KV (2005) Cilia and hedgehog responsiveness in the mouse. Proceedings of the National Academy of Sciences of the USA 102(32): 11325–11330.
    Huangfu D, Liu A, Rakeman AS et al. (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426(6962): 83–87.
    Hui CC and Angers S (2011) Gli proteins in development and disease. Annual Review of Cell and Developmental Biology 27: 513–537.
    Hui CC and Joyner AL (1993) A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intergenic deletion of the Gli3 gene. Nature Genetics 3(3): 241–246.
    Jiang J and Hui CC (2008) Hedgehog signaling in development and cancer. Developmental Cell 15(6): 801–812.
    Johnston JJ, Olivos-Glander I, Killoran C et al. (2005) Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister–Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. American Journal of Human Genetics 76(4): 609–622.
    Johnston JJ, Sapp JC, Turner JT et al. (2010) Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Human Mutation 31(10): 1142–1154.
    Kim PCW, Mo R and Hui CC (2001) Murine models of VACTERL syndrome: role of sonic hedgehog signaling pathway. Journal of Pediatric Surgery 36(2): 381–384.
    Kimura H, Stephen S, Joyner AL and Curran T (2005) Gli1 is important for medulloblastoma formation in Ptc1+/– mice. Oncogene 24(25): 4026–4036.
    ePath Li ZJ and Hui CC (2012) BCC and the secret lives of patched: insights from patched mouse models. In: Madan V (ed.) Basal Cell Carcinoma, pp. 608–609. ISBN: 978-953-51-0309-7, InTech. Available at http://www.intechopen.com/books/basal-cell-carcinoma/patching-the-gap-between-hh-signaling-and-bcc-insights-from-transgenic-mouse-models
    Li ZJ, Nieuwenhuis E, Nien W et al. (2012) Kif7 regulates Gli2 through Sufu-dependent and -independent mechanisms during epidermal development and tumorigenesis. Development 139: 4152–4161.
    Liem KF, Ashe A, He M et al. (2012) The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. Journal of Cell Biology 197(6): 789–800.
    Ming JE, Kaupas ME, Roessler E et al. (2002) Mutations in PATCHED-1, the receptor for sonic hedgehog, are associated with holoprosencephaly. Human Genetics 110(4): 297–301.
    Mo R, Freer AM and Zinyk DL et al. (1997) Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 124(1): 113–123.
    Mo R, Kim JH, Zhang J et al. (2001) Anorectal malformations caused by defects in sonic hedgehog signaling. American Journal of Pathology 159(2): 765–774.
    Motoyama J, Liu J and Mo R (1998) Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nature Genetics 20(1): 54–57.
    Nanni L, Ming JE, Bocian M et al. (1999) The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Human Molecular Genetics 8(13): 2479–2488.
    Nowaczyk MJ, Farrell SA, Sirkin WL et al. (2001) Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1GC genotype. American Journal of Medical Genetics 103(1): 75–80.
    Park HL, Bai C, Platt KA et al. (2000) Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127(8): 1593–1605.
    Pastorino L, Ghiorzo P, Nasti S et al. (2009) Identification of a SUFU germline mutation in a family with Gorlin syndrome. American Journal of Medical Genetics 149A(7): 1539–1543.
    Pineda-Alvarez DE, Roessler E, Hu P et al. (2012) Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH. Human Genetics 131(2): 301–310.
    Porter JA, Young KE and Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274(5285): 255–259.
    Putoux A, Thomas S, Coene KLM et al. (2011) KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nature Genetics 43(6): 601–606.
    Qin J, Lin Y, Norman RX, Ko HW and Eggenschwiler JT (2011) Intraflagellar transport protein 122 antagonizes sonic hedgehog signaling and controls ciliary localization of pathway components. Proceedings of the National Academy of Sciences of the USA 108(4): 1456–1461.
    Radhakrishna U, Blouin J, Mehenni H et al. (1997a) Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15–q11.23 by linkage analysis. American Journal of Human Genetics 60(3): 597–604.
    Radhakrishna U, Bornholdt D, Scott HS et al. (1999) The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations. American Journal of Human Genetics 65(3): 645–655.
    Radhakrishna U, Wild A, Grzeschik KH and Antonarakis SE (1997b) Mutation in GLI3 in postaxial polydactyly type A. Nature Genetics 17(3): 269–271.
    Rahimov F, Ribeiro LA, De Miranda E, Richieri-Costa A and Murray JC (2006) GLI2 Mutations in four Brazilian patients: how wide is the phenotypic spectrum? American Journal of Medical Genetics 140(23): 2571–2576.
    Rodríguez-Criado G, Magano L, Segovia M et al. (2005) Clinical and molecular studies on two further families with Simpson–Golabi–Behmel syndrome. American Journal of Medical Genetics 138A(3): 272–277.
    Roessler E, Du Y, Mullor JL et al. (2003) Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly like features. Proceedings of the National Academy of Sciences of the USA 100(23): 13424–13429.
    Sasaki H, Nishizaki Y, Hui CC, Nakafuku M and Kondoh H (1999) Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126(17): 3915–3924.
    Shin K, Lee J, Guo N et al. (2011) Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472(7341): 110–114.
    Smyth I, Narang MA, Evans T et al. (1999) Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32. Human Molecular Genetics 8(2): 291–297.
    Tukachinsky H, Lopez LV and Salic S (2010) A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes. Journal of Cell Biology 191(2): 415–428.
    Tuson M, He M and Anderson KV (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.
    Vierkotten J, Dildrop R, Peters T, Wang B and Rüther U (2007) Ftm is a novel basal body protein of cilia involved in Shh signalling. Development 134(14): 2569–2577.
 Further Reading
    Bitgood MJ, Shen L and McMahon AP (1996) Sertoli cell signaling by desert hedgehog regulates the male germline. Current Biology 6(3): 298–304.
    Cain JE, Islam E, Haxho F et al. (2009) GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells. PloS One 4(10): e7313.
    Gerdes JM, Davis EE and Katsanis N (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137(1): 32–45.
    Hu D and Marcucio RS (2009) A SHH-responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm. Development 136(1): 107–116.
    Hu MC, Mo R, Bhella S et al. (2006) GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development 133(3): 569–578.
    Joeng KS and Long F (2009) The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization. Development 136(24): 4177–4185.
    Lin AC, Seeto BL, Bartoszko JM et al. (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nature Medicine 15(12): 1421–1425.
    McMahon AP, Ingham PW and Tabin CJ (2003) Developmental roles and clinical significance of hedgehog signaling. Current Topics in Developmental Biology 53: 1–114.
    Swartz ME, Nguyen V, McCarthy NQ and Eberhart JK (2012) Hh signaling regulates patterning and morphogenesis of the pharyngeal arch-derived skeleton. Developmental Biology 369(1): 65–75.
    Weedon MN, Lango H, Lindgren CM et al. (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genetics 40(5): 575–583.

Related Sub-Topics:

Genes, Molecules and Cellular Processes | Developmental Disorders | Developmental Models | Model Organisms and Human Disease | Mutational Mechanisms of Genetic Disease | Transcriptional Regulation
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Article Title: GLI Proteins in Human Genetic Disease
 
How to Cite close
Olena, Zhulyn, and Chi‐chung, Hui(Dec 2012) GLI Proteins in Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024402]