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.

中文翻译：

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Wwox缺乏会导致小鼠神经发育和退行性神经病以及糖原合酶激酶3β介导的癫痫发作活性。

人WWOX基因位于染色体常见的易碎位点FRA16D中，并编码含有肿瘤抑制因子WW域的氧化还原酶。WWOX基因的两个等位基因中的功能丧失突变会导致来自血缘家庭的儿科患者的常染色体隐性遗传异常，包括小头畸形，小脑性共济失调伴癫痫，智力低下，视网膜变性，发育延迟和早期死亡。在这里，我们报道靶向破坏Wwox基因在小鼠中引起神经发育障碍，包括异常的神经元分化和大脑中的迁移。在Wwox-/-小鼠中观察到脑畸形，例如小头畸形和半球间部分裂，神经元紊乱和异位症，以及小脑中线融合不良，导致半球不完全分离。退行性改变包括中枢神经系统严重的髓鞘过少，视神经萎缩，小脑浦肯野细胞丢失和粒状细胞凋亡，以及由于施旺细胞凋亡引起的周围神经脱髓鞘，对应于振幅降低，经颅运动诱发电位潜伏期延长，运动缺陷和步态共济失调的Wwox-/-小鼠。Wwox基因消融导致断奶前小鼠自发性癫痫的发生和对毛果芸香碱和戊四氮（PTZ）诱发的癫痫发作的敏感性增加。我们确定Wwox-/-小鼠大脑皮层，海马和小脑中糖原合酶激酶3β（GSK3β）的激活显着增加。锂离子对GSK3β的抑制作用可显着消除Wwox-/-小鼠中PTZ诱发的癫痫发作。一起，