Role of Tumor Suppressor WWOX in Brain Development and Neurodegeneration

The WW domain-containing oxidoreductase (WWOX) gene maps to chromosomal fragile site FRA16D and behaves as a tumor suppressor. The high expression levels of the WWOX protein in the central nervous system (CNS), suggest a critical role for WWOX in CNS homeostasis. WWOX gene mutations were first associated with epilepsy and ataxia in animal models. Recent studies have demonstrated several germline WWOX mutations in patients with early onset of epilepsy, developmental retardation, intellectual deficiency, and the WOREE phenotype (WWOX-related epileptic encephalopathy), cerebellar ataxia and early death. More recently, several novel germline mutations were reported in children with early-onset epilepsy (EOE). In summary, homozygous and compound heterozygous WWOX mutations in human and in animal models cause a complex neurological syndrome underscoring a central role for WWOX in CNS development and epilepsy. In the current study we have focused on understanding the functional role of WWOX in brain homeostasis and physiology using mice models. We found that conditional deletion of murine Wwox in neuronal stem cells and progenitors (Wwox^ΔNestin) or neurons (Wwox^ΔSynapsin-I) phenocopies the same phenotypes of Wwox-null mice. Global growth retardation, hypoglycemia and post-natal lethality were reproduced in these newly generated mice. Importantly, these mice exhibited spontaneous seizures and ataxia. It should be stated that this is the first model of somatic Wwox-conditional ablation that reproduces all the phenotypes seen in Wwox-null mice. RNA-seq data and immunostaining experiments revealed severe hypomyelination in all parts of the brain linking WWOX loss with non-cell autonomous reduction in mature oligodendrocytes. Electrophysiological recordings from the hippocampus region revealed epileptic spikes that are associated with seizures. These results indicate that WWOX is playing a vital role in maintaining the CNS homeostasis and that its absence in neurons of the CNS leads to a complex neurological phenotype.