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PMID:21959375

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Citation

Simms, RJ, Hynes, AM, Eley, L, Inglis, D, Chaudhry, B, Dawe, HR and Sayer, JA (2012) Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development. Cell. Mol. Life Sci. 69:993-1009

Abstract

Joubert syndrome and related diseases (JSRD) are cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy, and nephronophthisis (a cystic kidney disease). Mutations in AHI1 are the most common genetic cause of JSRD, with developmental hindbrain anomalies and retinal degeneration being prominent features. We demonstrate that Ahi1, a WD40 domain-containing protein, is highly conserved throughout evolution and its expression associates with ciliated organisms. In zebrafish ahi1 morphants, the phenotypic spectrum of JSRD is modeled, with embryos showing brain, eye, and ear abnormalities, together with renal cysts and cloacal dilatation. Following ahi1 knockdown in zebrafish, we demonstrate loss of cilia at Kupffer's vesicle and subsequently defects in cardiac left-right asymmetry. Finally, using siRNA in renal epithelial cells we demonstrate a role for Ahi1 in both ciliogenesis and cell-cell junction formation. These data support a role for Ahi1 in epithelial cell organization and ciliary formation and explain the ciliopathy phenotype of AHI1 mutations in man.

Links

PubMed Online version:10.1007/s00018-011-0826-z

Keywords

Amino Acid Sequence; Animals; Biological Evolution; Brain/embryology; Carrier Proteins/physiology; Cell Polarity; Cells, Cultured; Cilia/pathology; Cilia/physiology; Kidney/embryology; Mice; Molecular Sequence Data; Proto-Oncogene Proteins/chemistry; Proto-Oncogene Proteins/physiology; Retina/embryology; Zebrafish/embryology; Zebrafish Proteins/physiology

Significance

Annotations

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

DANRE:B3DJG1

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:B3DJG1

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:F1QX08

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:F1QX08

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:F8W3V6

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:F8W3V6

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:F8W4S4

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:F8W4S4

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120314-2

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0001947: heart looping

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0007417: central nervous system development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0030902: hindbrain development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0010842: retina layer formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

located_in

GO:0005929: cilium

ECO:0000305: curator inference used in manual assertion

GO:0060271

C

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0070121: Kupffer's vesicle development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0065001: specification of axis polarity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0005310)

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0071599: otic vesicle development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0070986: left/right axis specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0039023: pronephric duct morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0039008: pronephric nephron tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:Q07DM1

involved_in

GO:0035844: cloaca development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0001738: morphogenesis of a polarized epithelium

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002518)

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0005929: cilium

ECO:0000305: curator inference used in manual assertion

GO:0060271

C

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0039008: pronephric nephron tubule morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0065001: specification of axis polarity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0071599: otic vesicle development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0001947: heart looping

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0005929: cilium

ECO:0000305: curator inference used in manual assertion

GO:0060271

C

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0007417: central nervous system development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0010842: retina layer formation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0030862: positive regulation of polarized epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0030902: hindbrain development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0035844: cloaca development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:F8W3V6

P

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0001738: morphogenesis of a polarized epithelium

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002518)

Seeded From UniProt

complete


See also

References

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