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PMID:16254602

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Citation

Haycraft, CJ, Banizs, B, Aydin-Son, Y, Zhang, Q, Michaud, EJ and Yoder, BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 1:e53

Abstract

Intraflagellar transport (IFT) proteins are essential for cilia assembly and have recently been associated with a number of developmental processes, such as left-right axis specification and limb and neural tube patterning. Genetic studies indicate that IFT proteins are required for Sonic hedgehog (Shh) signaling downstream of the Smoothened and Patched membrane proteins but upstream of the Glioma (Gli) transcription factors. However, the role that IFT proteins play in transduction of Shh signaling and the importance of cilia in this process remain unknown. Here we provide insights into the mechanism by which defects in an IFT protein, Tg737/Polaris, affect Shh signaling in the murine limb bud. Our data show that loss of Tg737 results in altered Gli3 processing that abrogates Gli3-mediated repression of Gli1 transcriptional activity. In contrast to the conclusions drawn from genetic analysis, the activity of Gli1 and truncated forms of Gli3 (Gli3R) are unaffected in Tg737 mutants at the molecular level, indicating that Tg737/Polaris is differentially involved in specific activities of the Gli proteins. Most important, a negative regulator of Shh signaling, Suppressor of fused, and the three full-length Gli transcription factors localize to the distal tip of cilia in addition to the nucleus. Thus, our data support a model where cilia have a direct role in Gli processing and Shh signal transduction.

Links

PubMed PMC1270009 Online version:10.1371/journal.pgen.0010053

Keywords

Animals; Extremities/embryology; Flagella/metabolism; Hedgehog Proteins; Kruppel-Like Transcription Factors/genetics; Kruppel-Like Transcription Factors/physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/physiology; Trans-Activators/metabolism; Transcription Factors/metabolism; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GLI1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI2

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:IFT88

located_in

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:32705)|part_of:(EMAPA:35944)|part_of:(EMAPA:32708)

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0070613: regulation of protein processing

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1859153

P

  • has_input:(UniProtKB:Q61602)

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:1905515: non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2157527

P

  • occurs_in:(EMAPA:35944)

Seeded From UniProt

complete

MOUSE:GLI3

located_in

GO:0005634: nucleus

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P10071

C

Seeded From UniProt

complete

MOUSE:GLI3

located_in

GO:0005929: cilium

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P10071

C

Seeded From UniProt

complete

MOUSE:SUFU

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SUFU

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI2

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI2

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314:

P

Gli2 increased transcription of Ptch1 in wild type cells (Figure 3B).

complete
CACAO 10676

MOUSE:GLI3

acts_upstream_of_or_within

GO:0042733: embryonic digit morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856276

P

Seeded From UniProt

complete

MOUSE:GLI3

part_of

GO:0005929: cilium

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P10071

C

Seeded From UniProt

complete

MOUSE:GLI3

part_of

GO:0005634: nucleus

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P10071

C

Seeded From UniProt

complete

MOUSE:GLI3

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856276

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:1905515: non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2157527

P

occurs_in:(EMAPA:35944)

Seeded From UniProt

complete

MOUSE:IFT88

part_of

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:35944)
  • part_of:(EMAPA:32705)|part_of:(EMAPA:35944)
  • part_of:(EMAPA:32708)

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0070613: regulation of protein processing

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1859153

P

has_direct_input:(UniProtKB:Q61602)

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0042733: embryonic digit morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2157527

P

Seeded From UniProt

complete

MOUSE:IFT88

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315:

P

In the absence of Polaris, Gli2 expressing wild type cells show reduced levels of Ptch1 transcription (Figure 3B).

complete
CACAO 10673

MOUSE:SUFU

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SUFU

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005930: axoneme

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

colocalizes_with

GO:0097542: ciliary tip

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314:

P

Gli1 increased transcription of Ptch1 compared to the GFP control in limb bud cells (Figure 3A).

complete
CACAO 10671

MOUSE:GLI1

GO:0005930: axoneme

ECO:0000314:

C

Figure 5A shows Gli1 localization in the cilium axoneme.

complete
CACAO 10699

MOUSE:GLI1

Colocalizes with

GO:0097542: ciliary tip

ECO:0000314:

C

Figure 5 shows ciliary tip localization due to failure of GFP to colocalize with gamma-tubulin in addition to colocalizing within a domain of Polaris.

complete
CACAO 10718

HUMAN:GLI3

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314:

P

Gli3 represses Gli1, which induces Ptch1 transcription, therefore Gli3 reduces Ptch1 transcription (Figure 3D).

complete
CACAO 10739

HUMAN:GLI3

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GLI3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GLI3

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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