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PMID:22210625

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Citation

Ramirez, IB, Pietka, G, Jones, DR, Divecha, N, Alia, A, Baraban, SC, Hurlstone, AF and Lowe, M (2012) Impaired neural development in a zebrafish model for Lowe syndrome. Hum. Mol. Genet. 21:1744-59

Abstract

Lowe syndrome, which is characterized by defects in the central nervous system, eyes and kidneys, is caused by mutation of the phosphoinositide 5-phosphatase OCRL1. The mechanisms by which loss of OCRL1 leads to the phenotypic manifestations of Lowe syndrome are currently unclear, in part, owing to the lack of an animal model that recapitulates the disease phenotype. Here, we describe a zebrafish model for Lowe syndrome using stable and transient suppression of OCRL1 expression. Deficiency of OCRL1, which is enriched in the brain, leads to neurological defects similar to those reported in Lowe syndrome patients, namely increased susceptibility to heat-induced seizures and cystic brain lesions. In OCRL1-deficient embryos, Akt signalling is reduced and there is both increased apoptosis and reduced proliferation, most strikingly in the neural tissue. Rescue experiments indicate that catalytic activity and binding to the vesicle coat protein clathrin are essential for OCRL1 function in these processes. Our results indicate a novel role for OCRL1 in neural development, and support a model whereby dysregulation of phosphoinositide metabolism and clathrin-mediated membrane traffic leads to the neurological symptoms of Lowe syndrome.

Links

PubMed PMC3313792 Online version:10.1093/hmg/ddr608

Keywords

Animals; Brain/embryology; Brain/pathology; Cell Survival; Clathrin/metabolism; Disease Models, Animal; Embryo, Nonmammalian; Embryonic Development; Endosomes/metabolism; Gene Expression Profiling; Golgi Apparatus/metabolism; Hot Temperature; Oculocerebrorenal Syndrome; Phosphatidylinositol 4,5-Diphosphate/metabolism; Phosphoric Monoester Hydrolases/genetics; Phosphoric Monoester Hydrolases/metabolism; Protein Splicing; Proto-Oncogene Proteins c-akt/metabolism; Seizures/physiopathology; Signal Transduction; Zebrafish/embryology; Zebrafish/genetics; Zebrafish/growth & development; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

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

DANRE:A0A0R4IPY6

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120405-1

P

Seeded From UniProt

complete

DANRE:A0A0R4IPY6

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0A0R4IPY6

enables

GO:0004439: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

F

Seeded From UniProt

complete

DANRE:A0A0R4IPY6

involved_in

GO:0046856: phosphatidylinositol dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0A2R8QCJ2

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120405-1

P

Seeded From UniProt

complete

DANRE:A0A2R8QCJ2

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0A2R8QCJ2

enables

GO:0004439: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

F

Seeded From UniProt

complete

DANRE:A0A2R8QCJ2

involved_in

GO:0046856: phosphatidylinositol dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0A2R8QMS0

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120405-1

P

Seeded From UniProt

complete

DANRE:A0A2R8QMS0

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0A2R8QMS0

enables

GO:0004439: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

F

Seeded From UniProt

complete

DANRE:A0A2R8QMS0

involved_in

GO:0046856: phosphatidylinositol dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0JMC7

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120405-1

P

Seeded From UniProt

complete

DANRE:A0JMC7

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:A0JMC7

enables

GO:0004439: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

F

Seeded From UniProt

complete

DANRE:A0JMC7

involved_in

GO:0046856: phosphatidylinositol dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:F1QIY4

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120405-1

P

Seeded From UniProt

complete

DANRE:F1QIY4

involved_in

GO:0007420: brain development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete

DANRE:F1QIY4

enables

GO:0004439: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

F

Seeded From UniProt

complete

DANRE:F1QIY4

involved_in

GO:0046856: phosphatidylinositol dephosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-120531-1

P

Seeded From UniProt

complete


See also

References

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