Data_Sheet_1_Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development.pdf (2.33 MB)
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Data_Sheet_1_Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development.pdf

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posted on 11.06.2020, 04:12 by Michele Iacomino, Simona Baldassari, Yuki Tochigi, Katarzyna Kośla, Francesca Buffelli, Annalaura Torella, Mariasavina Severino, Dario Paladini, Luana Mandarà, Antonella Riva, Marcello Scala, Ganna Balagura, Andrea Accogli, Vincenzo Nigro, Carlo Minetti, Ezio Fulcheri, Federico Zara, Andrzej K. Bednarek, Pasquale Striano, Hiroetsu Suzuki, Vincenzo Salpietro

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.

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