Iacomino, M;
Baldassari, S;
Tochigi, Y;
Kośla, K;
Buffelli, F;
Torella, A;
Severino, M;
... Salpietro, V; + view all
(2020)
Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development.
Frontiers in Neuroscience
, 14
(644)
10.3389/fnins.2020.00644.
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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.
| Type: | Article |
|---|---|
| Title: | Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fnins.2020.00644 |
| Publisher version: | http://dx.doi.org/10.3389/fnins.2020.00644 |
| Language: | English |
| Additional information: | © 2020 Iacomino, Baldassari, Tochigi, Kośla, Buffelli, Torella, Severino, Paladini, Mandarà, Riva, Scala, Balagura, Accogli, Nigro, Minetti, Fulcheri, Zara, Bednarek, Striano, Suzuki and Salpietro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10114931 |
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