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PMID:19036983

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Citation

Willaredt, MA, Hasenpusch-Theil, K, Gardner, HA, Kitanovic, I, Hirschfeld-Warneken, VC, Gojak, CP, Gorgas, K, Bradford, CL, Spatz, J, Wölfl, S, Theil, T and Tucker, KL (2008) A crucial role for primary cilia in cortical morphogenesis. J. Neurosci. 28:12887-900

Abstract

Primary cilia are important sites of signal transduction involved in a wide range of developmental and postnatal functions. Proteolytic processing of the transcription factor Gli3, for example, occurs in primary cilia, and defects in intraflagellar transport (IFT), which is crucial for the maintenance of primary cilia, can lead to severe developmental defects and diseases. Here we report an essential role of primary cilia in forebrain development. Uncovered by N-ethyl-N-nitrosourea-mutagenesis, cobblestone is a hypomorphic allele of the IFT gene Ift88, in which Ift88 mRNA and protein levels are reduced by 70-80%. cobblestone mutants are distinguished by subpial heterotopias in the forebrain. Mutants show both severe defects in the formation of dorsomedial telencephalic structures, such as the choroid plexus, cortical hem and hippocampus, and also a relaxation of both dorsal-ventral and rostral-caudal compartmental boundaries. These defects phenocopy many of the abnormalities seen in the Gli3 mutant forebrain, and we show that Gli3 proteolytic processing is reduced, leading to an accumulation of the full-length activator isoform. In addition, we observe an upregulation of canonical Wnt signaling in the neocortex and in the caudal forebrain. Interestingly, the ultrastructure and morphology of ventricular cilia in the cobblestone mutants remains intact. Together, these results indicate a critical role for ciliary function in the developing forebrain.

Links

PubMed Online version:10.1523/JNEUROSCI.2084-08.2008

Keywords

Animals; Cerebral Cortex/abnormalities; Cerebral Cortex/metabolism; Cerebral Cortex/ultrastructure; Cilia/metabolism; Cilia/ultrastructure; Ependyma/metabolism; Ependyma/ultrastructure; Female; Gene Expression Regulation, Developmental/genetics; Kruppel-Like Transcription Factors/genetics; Kruppel-Like Transcription Factors/metabolism; Lateral Ventricles/abnormalities; Lateral Ventricles/metabolism; Lateral Ventricles/ultrastructure; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Neurons/metabolism; Neurons/ultrastructure; Peptide Hydrolases/metabolism; Prosencephalon/abnormalities; Prosencephalon/metabolism; Prosencephalon/ultrastructure; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Wnt Proteins/metabolism

Significance

Annotations

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

MOUSE:NEST

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000540)

Seeded From UniProt

complete

MOUSE:TBB3

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000540)

Seeded From UniProt

complete

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

acts_upstream_of_or_within

GO:0021537: telencephalon development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856276

P

Seeded From UniProt

complete

MOUSE:GLI3

acts_upstream_of_or_within

GO:0016485: protein processing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0060426: lung vasculature development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0060411: cardiac septum morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0048853: forebrain morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

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:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0030324: lung development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0021537: telencephalon development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0007399: nervous system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete

MOUSE:IFT88

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3823090

P

Seeded From UniProt

complete


See also

References

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