Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
1999 Mar 16;966:2880-4. doi: 10.1073/pnas.96.6.2880.
Show Gene links
Show Anatomy links
GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization.
Shin SH, Kogerman P, Lindström E, Toftgárd R, Biesecker LG.
???displayArticle.abstract???
Truncation mutations of the GLI3 zinc finger transcription factor can cause Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS), and postaxial polydactyly type A (PAP-A). GLI3 is homologous to Drosophila Cubitus interruptus (Ci), which regulates the patched (ptc), gooseberry (gsb), and decapentaplegic (dpp) genes. Ci is sequestered in the cytoplasm and is subject to posttranslational processing whereby the full-length transcriptional activator form (Ci155) can be cleaved to a repressor form (Ci75). Under hedgehog signaling, the Ci155 form translocates to the nucleus whereas in the absence of hedgehog, the Ci75 form translocates to the nucleus. Based on the correlation of GLI3 truncation mutations and the human phenotypes, we hypothesized that GLI3 shows transcriptional activation or repression activity and subcellular localization similar to Ci. Here we show that full-length GLI3 localizes to the cytoplasm and activates PTCH1 expression, which is similar to full-length Ci155. PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression, which is similar to Ci75. The GCPS mutant protein has no effect on GLI3-activated PTCH1 transcription, consistent with the role of haploinsufficiency in this disorder. The PAP-A mutant protein (GLI3-PAP-A) showed less specific subcellular localization but still inhibited GLI3-activated PTCH1 transcription, suggesting it may be a weaker allele than the GLI3-PHS mutation. These data show that GLI3 mutations in humans mimic functional effects of the Drosophila ci gene and correlate with the distinct effects of these mutations on human development.
Aza-Blanc,
Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
1997, Pubmed
Aza-Blanc,
Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
1997,
Pubmed Biesecker,
Strike three for GLI3.
1997,
Pubmed
,
Xenbase Biesecker,
Pallister-Hall syndrome.
1996,
Pubmed Büscher,
Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development.
1997,
Pubmed
,
Xenbase Chang,
Axial (HNF3beta) and retinoic acid receptors are regulators of the zebrafish sonic hedgehog promoter.
1997,
Pubmed Finnigan,
Extending the Pallister-Hall syndrome to include other central nervous system malformations.
1991,
Pubmed Hahn,
Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.
1996,
Pubmed Kang,
GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.
1997,
Pubmed
,
Xenbase Knezevic,
Hoxd-12 differentially affects preaxial and postaxial chondrogenic branches in the limb and regulates Sonic hedgehog in a positive feedback loop.
1997,
Pubmed Lee,
Gli1 is a target of Sonic hedgehog that induces ventral neural tube development.
1997,
Pubmed
,
Xenbase Liu,
Carboxy-terminally truncated Gli3 proteins associate with Smads.
1998,
Pubmed
,
Xenbase Masuya,
Multigenic control of the localization of the zone of polarizing activity in limb morphogenesis in the mouse.
1997,
Pubmed
,
Xenbase Monnier,
Suppressor of fused links fused and Cubitus interruptus on the hedgehog signalling pathway.
1998,
Pubmed Radhakrishna,
Mutation in GLI3 in postaxial polydactyly type A.
1997,
Pubmed
,
Xenbase Robbins,
Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2.
1997,
Pubmed Ruiz i Altaba,
Catching a Gli-mpse of Hedgehog.
1997,
Pubmed Ruppert,
GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity.
1990,
Pubmed
,
Xenbase Sasaki,
A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro.
1997,
Pubmed
,
Xenbase Vortkamp,
GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families.
1991,
Pubmed
,
Xenbase Vortkamp,
Identification of optimized target sequences for the GLI3 zinc finger protein.
1995,
Pubmed
,
Xenbase Wild,
Point mutations in human GLI3 cause Greig syndrome.
1997,
Pubmed
,
Xenbase Yoon,
GLI activates transcription through a herpes simplex viral protein 16-like activation domain.
1998,
Pubmed
