AUTHOR=Iacomino Michele , Baldassari Simona , Tochigi Yuki , Kośla Katarzyna , Buffelli Francesca , Torella Annalaura , Severino Mariasavina , Paladini Dario , Mandarà Luana , Riva Antonella , Scala Marcello , Balagura Ganna , Accogli Andrea , Nigro Vincenzo , Minetti Carlo , Fulcheri Ezio , Zara Federico , Bednarek Andrzej K. , Striano Pasquale , Suzuki Hiroetsu , Salpietro Vincenzo TITLE=Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development JOURNAL=Frontiers in Neuroscience VOLUME=14 YEAR=2020 URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2020.00644 DOI=10.3389/fnins.2020.00644 ISSN=1662-453X ABSTRACT=

Mutations in the WWOX gene 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 homozygous WWOX mutation 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 a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (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 the WWOX gene in migrating neurons across different species.