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PMID:21653639

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Citation

Friedland-Little, JM, Hoffmann, AD, Ocbina, PJ, Peterson, MA, Bosman, JD, Chen, Y, Cheng, SY, Anderson, KV and Moskowitz, IP (2011) A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum. Mol. Genet. 20:3725-37

Abstract

The primary cilium is emerging as a crucial regulator of signaling pathways central to vertebrate development and human disease. We identified atrioventricular canal 1 (avc1), a mouse mutation that caused VACTERL association with hydrocephalus, or VACTERL-H. We showed that avc1 is a hypomorphic mutation of intraflagellar transport protein 172 (Ift172), required for ciliogenesis and Hedgehog (Hh) signaling. Phenotypically, avc1 caused VACTERL-H but not abnormalities in left-right (L-R) axis formation. Avc1 resulted in structural cilia defects, including truncated cilia in vivo and in vitro. We observed a dose-dependent requirement for Ift172 in ciliogenesis using an allelic series generated with Ift172(avc1) and Ift172(wim), an Ift172 null allele: cilia were present on 42% of avc1 mouse embryonic fibroblast (MEF) and 28% of avc1/wim MEFs, in contrast to >90% of wild-type MEFs. Furthermore, quantitative cilium length analysis identified two specific cilium populations in mutant MEFS: a normal population with normal IFT and a truncated population, 50% of normal length, with disrupted IFT. Cells from wild-type embryos had predominantly full-length cilia, avc1 embryos, with Hh signaling abnormalities but not L-R abnormalities, had cilia equally divided between full-length and truncated, and avc1/wim embryos, with both Hh signaling and L-R abnormalities, were primarily truncated. Truncated Ift172 mutant cilia showed defects of the distal ciliary axoneme, including disrupted IFT88 localization and Hh-dependent Gli2 localization. We propose a model in which mutation of Ift172 results in a specific class of abnormal cilia, causing disrupted Hh signaling while maintaining L-R axis determination, and resulting in the VACTERL-H phenotype.

Links

PubMed PMC3168284 Online version:10.1093/hmg/ddr241

Keywords

Alleles; Anal Canal/abnormalities; Anal Canal/embryology; Anal Canal/metabolism; Animals; Cilia/genetics; Cilia/metabolism; Disease Models, Animal; Esophagus/abnormalities; Esophagus/embryology; Esophagus/metabolism; Heart Defects, Congenital/embryology; Heart Defects, Congenital/genetics; Heart Defects, Congenital/metabolism; Hedgehog Proteins/genetics; Hedgehog Proteins/metabolism; Humans; Hydrocephalus/embryology; Hydrocephalus/genetics; Hydrocephalus/metabolism; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Kidney/abnormalities; Kidney/embryology; Kidney/metabolism; Limb Deformities, Congenital/embryology; Limb Deformities, Congenital/genetics; Limb Deformities, Congenital/metabolism; Mice/genetics; Mice/metabolism; Mice, Inbred C3H; Mice, Inbred C57BL; Mutagenesis; Mutation; Protein Transport; Signal Transduction/genetics; Spine/abnormalities; Spine/embryology; Spine/metabolism; Trachea/abnormalities; Trachea/embryology; Trachea/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Significance

Annotations

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

MOUSE:GLI2

located_in

GO:0097542: ciliary tip

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:IFT88

located_in

GO:0097542: ciliary tip

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:IFT88

located_in

GO:0097546: ciliary base

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0008589: regulation of smoothened signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:16039)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0007507: heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0061525: hindgut development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:17898)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0060348: bone development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:17674)|occurs_in:(EMAPA:35495)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:16075)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0060173: limb development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:16405)

Seeded From UniProt

complete

MOUSE:IF172

acts_upstream_of_or_within

GO:0060021: roof of mouth development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4821824

P

  • occurs_in:(EMAPA:18948)

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0097542: ciliary tip

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:IFT88

part_of

GO:0097546: ciliary base

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:IFT88

part_of

GO:0097542: ciliary tip

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

Notes

See also

References

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