Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Abstract

Abstract Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox −/− mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox −/− mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine- and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3β (GSK3β) occurs in Wwox −/− mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3β by lithium ion significantly abolishes the onset of PTZ-induced seizure in Wwox −/− mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3β with lithium ion ameliorates epilepsy.

Keywords

• Common chromosomal fragile site
• Brain malformations
• Neuronal degeneration
• Schwann cell apoptosis
• Epilepsy