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.
Highlights
Common fragile sites are large chromosomal regions that tend to form gaps or breaks under replication stress
Southern blot analysis using genomic DNA isolated from mouse embryonic fibroblasts (MEF) and polymerase chain reactions using mouse tail DNA demonstrated that Wwox gene was disrupted in both Wwox gene exon-1 deletion (WD1) and Wwox gene exon-2/3/4 deletion (WD234) mice (Additional file 1: Figure S1a, b)
Our data showed that the stride length, hind-base width, and hind-to-fore base ratio were significantly decreased in Wwox−/− mice (Fig. 1d, e)
Summary
Common fragile sites are large chromosomal regions that tend to form gaps or breaks under replication stress. Genomic instability and alterations at the chromosomal fragile sites have been implicated as being causative for many types of human cancers [23]. Human WWOX gene is mapped to a common fragile site FRA16D on chromosome 16q23.3–24.1, and encodes a tumor suppressor WW domain-containing oxidoreductase, WWOX [11, 17, 56]. WWOX protein expression is significantly downregulated in the hippocampal neurons of patients with Alzheimer’s disease [59]. Suppression of WWOX expression by small interfering RNA induces Tau hyperphosphorylation and formation of neurofibrillary tangles in neuroblastoma SK-N-SH cells, suggesting a crucial role of WWOX in inhibiting Tau phosphorylation in the degenerative neurons of Alzheimer’s disease [15, 58, 59]. WWOX has been demonstrated to exert its functions through regulating many signaling molecules, the vital requirements for WWOX in vivo remain largely undefined
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