Ramirez, I.B., Pietka, G., Jones, D.R., Divecha, N., Aliam, A., Baraban, S.C., Hurlstone, A.F., and Lowe, M. (2012) Impaired Neural Development in a Zebrafish Model for Lowe Syndrome. Human molecular genetics. 21(8):1744-1759.
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.