GLI Proteins in Human Genetic Disease


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, ). Annotated Pallister–Hall syndrome (PHS) and Greig cephalopolysyndactyly syndrome (GCPS) mutations were described by Johnston et al. ; 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. . Acrocallosal syndrome (ACLS) mutation was described by Elson et al. . Nonsyndromic preaxial polydacytly type IV and type I (PPDIV and PPDI) were described in Fujioka et al. and Radhakrishna et al. . Nonsyndromic postaxial polydactyly type A and B (PAPA/B) were described by Radhakrishna et al. .

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, ; Jiang and Hui, ). 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 Gli3Δ699699 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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Further Reading

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Olena, Zhulyn, and Chi‐chung, Hui(Dec 2012) GLI Proteins in Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024402]