Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development
Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development
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DOI：
10.3389/fnins.2020.00644
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发表时间：
2020-06-11
影响因子：
4.3
通讯作者：
Salpietro, Vincenzo
中科院分区：
文献类型：
--
作者：
Iacomino, Michele;Baldassari, Simona;Salpietro, Vincenzo
WWOX基因的突变会导致一系列极其罕见的神经发育和脑退行性疾病，这些疾病与动物模型和人类中过早死亡的可能性很高有关。编码的Wwox蛋白是一种含有WW结构域的氧化还原酶，其参与重要的生物学过程，包括肿瘤抑制、细胞生长/分化和类固醇代谢的调节，而其在神经发育中的作用尚不清楚。我们分析了一个患有多种产前和产后异常的家族的外显子组，包括小脑蚓部发育不全，严重的神经发育障碍和难治性癫痫，并确定了一个分离的同源WWOX突变导致过早的终止密码子。在来自该家族的aWWOX缺陷型人类胎儿的发育中的脑中发现了由于颗粒和分子细胞层的结构缺陷而导致的异常大脑皮质发育。在围产期研究的lde/lderats（携带破坏活性Wwox C-末端结构域的纯合截短突变）中发现了类似的皮质层紊乱。Wwox缺失的人神经前体细胞的转录组学分析显示，编码微管蛋白、驱动蛋白和相关蛋白的一些神经元迁移相关基因的表达受损。这些研究结果表明，Wwox的损失可能会影响不同的细胞骨架成分，改变产前皮质发育，突出了WWOX基因在不同物种间迁移神经元的调节作用。
Mutations in theWWOXgene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygousWWOXmutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of aWWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified inlde/lderats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of theWWOXgene in migrating neurons across different species.