Impaired neural development in a zebrafish model for Lowe syndrome

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.

RNA polymerase III component Rpc9 regulates hematopoietic stem and progenitor cell maintenance in zebrafish

“…These dividing cells require rapid biological macromolecule synthesis, including RNA transcription and protein synthesis and this is implicated in elevated Pol III activity (Goodfellow and White, 2007;Signer et al, 2014), which is tightly regulated and vulnerable to alteration of intrinsic network or environment cues (Goodfellow and White, 2007;Boguta and Graczyk, 2011;Acker et al, 2014). Notably, tissues with a high proliferation rate, including central nervous and hematopoietic systems, display hypersensitivity to adverse genetic mutations (Zaros and Thuriaux, 2005;Li et al, 2012;Ramirez et al, 2012;Belle et al, 2015), which is in line with the impairment of survival and proliferation of HSPCs observed in rpc9 −/− embryos. The CGRP receptor complex, which includes Rpc9, has previously been shown to be expressed on human CD34 + cells and is required for granulopoiesis (Harzenetter et al, 2002).…”

Epilepsy research methods update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms

“…ocrl1 homozygous mutant adult zebrafish develop gliosis and cystic brain lesions reminiscent of those in Lowe Syndrome patients, and mutant larvae exhibit temperature-sensitive electrographic seizure-like activity in the developing brain. 84 The development of a larval zebrafish model for Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy (EAST) syndrome, 85 also known as Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance (SeSAME) syndrome, 86 offers new hope for improved understanding of the pathogenetic mechanisms underlying this disorder. This syndrome is caused by mutations in an inwardly-rectifying potassium channel called KCNJ10 (previously known as Kir4.1), which most likely cause partial loss-of-function phenotypes.…”

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

“…It combines easy handling and relatively high-throughput screening with the complexity of a whole vertebrate organism. Within the past decade, the usefulness of zebrafish in epilepsy research has been validated through studies involving pharmacologically induced acute seizure models [13][14][15] as well as zebrafish models of genetic epileptic syndromes (Angelman's [16], Lowe's [17], BNFC [18], EAST [19], and Dravet [20,21]). More recently, some of these zebrafish models have been applied in high-throughput epilepsy drug discovery (PTZ [22] and Dravet [20]).…”