ZFIN ID: ZDB-PUB-120111-6
Impaired Neural Development in a Zebrafish Model for Lowe Syndrome
Ramirez, I.B., Pietka, G., Jones, D.R., Divecha, N., Aliam, A., Baraban, S.C., Hurlstone, A.F., and Lowe, M.
Date: 2012
Source: Human molecular genetics   21(8): 1744-1759 (Journal)
Registered Authors: Hurlstone, Adam, Lowe, Martin, Pietka, Grzegorz
Keywords: none
MeSH Terms:
  • 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
PubMed: 22210625 Full text @ Hum. Mol. Genet.

Lowe syndrome, which is characterised 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 due 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.