GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization.

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.

• Authors: S H Shin, P Kogerman, E Lindström, R Toftgárd, L G Biesecker
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 96 Issue 6 Pg. 2880-4 (Mar 16 1999) ISSN: 0027-8424 [Print] United States
• PMID: 10077605 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Drosophila Proteins
• GLI3 protein, Xenopus
• GLI3 protein, human
• Gli3 protein, mouse
• Kruppel-Like Transcription Factors
• Nerve Tissue Proteins
• Repressor Proteins
• Transcription Factors
• Xenopus Proteins
• Zinc Finger Protein Gli3
• ci protein, Drosophila

Topics

• Animals
• DNA-Binding Proteins (genetics)
• Drosophila
• Drosophila Proteins
• Humans
• Kruppel-Like Transcription Factors
• Mutation
• Nerve Tissue Proteins (genetics)
• Polydactyly (genetics)
• Repressor Proteins
• Syndrome
• Transcription Factors (genetics)
• Transcriptional Activation
• Xenopus Proteins
• Zinc Finger Protein Gli3
• Zinc Fingers (genetics)