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PMID:22228095

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Citation

Ashe, A, Butterfield, NC, Town, L, Courtney, AD, Cooper, AN, Ferguson, C, Barry, R, Olsson, F, Liem, KF Jr, Parton, RG, Wainwright, BJ, Anderson, KV, Whitelaw, E and Wicking, C (2012) Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies. Hum. Mol. Genet. 21:1808-23

Abstract

Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene. The mutant twinkle-toes (Ift144(twt)) phenocopies a number of the skeletal and craniofacial anomalies seen in patients with human skeletal ciliopathies. Like other IFT-A mouse mutants, Ift144 mutant embryos display a generalized ligand-independent expansion of hedgehog (Hh) signalling, in spite of defective ciliogenesis and an attenuation of the ability of mutant cells to respond to upstream stimulation of the pathway. This enhanced Hh signalling is consistent with cleft palate and polydactyly phenotypes in the Ift144(twt) mutant, although extensive rib branching, fusion and truncation phenotypes correlate with defects in early somite patterning and may reflect contributions from multiple signalling pathways. Analysis of embryos harbouring a second allele of Ift144 which represents a functional null, revealed a dose-dependent effect on limb outgrowth consistent with the short-limb phenotypes characteristic of these ciliopathies. This allelic series of mouse mutants provides a unique opportunity to uncover the underlying mechanistic basis of this intriguing subset of ciliopathies.

Links

PubMed PMC3313797 Online version:10.1093/hmg/ddr613

Keywords

Abnormalities, Multiple/embryology; Abnormalities, Multiple/genetics; Abnormalities, Multiple/metabolism; Animals; Chromosome Mapping; Cilia/physiology; Cilia/ultrastructure; Craniofacial Abnormalities/embryology; Craniofacial Abnormalities/genetics; Craniofacial Abnormalities/metabolism; Embryo, Mammalian; Fibroblast Growth Factors/metabolism; Forelimb/abnormalities; Forelimb/metabolism; Hedgehog Proteins/metabolism; Intercellular Signaling Peptides and Proteins/metabolism; Mice; Mutagenesis; Mutation, Missense; Phenotype; Polydactyly/embryology; Polydactyly/genetics; Polydactyly/metabolism; Proteins/chemistry; Proteins/genetics; Ribs/abnormalities; Signal Transduction

Significance

Annotations

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

MOUSE:WDR19

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747
MGI:MGI:5315748

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0000902: cell morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315748

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747
MGI:MGI:5315748

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0031076: embryonic camera-type eye development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0030326: embryonic limb morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747
MGI:MGI:5315748

P

Seeded From UniProt

complete

MOUSE:WDR19

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0050877: nervous system process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0061055: myotome development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747
MGI:MGI:5315748

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0055123: digestive system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747

P

Seeded From UniProt

complete

MOUSE:WDR19

acts_upstream_of_or_within

GO:0042471: ear morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5315747

P

Seeded From UniProt

complete


See also

References

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