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      Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development


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          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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          Most cited references48

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          Data quality aware analysis of differential expression in RNA-seq with NOISeq R/Bioc package

          As the use of RNA-seq has popularized, there is an increasing consciousness of the importance of experimental design, bias removal, accurate quantification and control of false positives for proper data analysis. We introduce the NOISeq R-package for quality control and analysis of count data. We show how the available diagnostic tools can be used to monitor quality issues, make pre-processing decisions and improve analysis. We demonstrate that the non-parametric NOISeqBIO efficiently controls false discoveries in experiments with biological replication and outperforms state-of-the-art methods. NOISeq is a comprehensive resource that meets current needs for robust data-aware analysis of RNA-seq differential expression.
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            Tbr1 regulates differentiation of the preplate and layer 6.

            During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.
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              Physical biology of human brain development

              Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales–from phenomena on the cellular level toward form and function on the organ level–to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.

                Author and article information

                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                11 June 2020
                : 14
                [1] 1Unit of Medical Genetics, IRCCS Istituto “Giannina Gaslini” , Genoa, Italy
                [2] 2Laboratory of Veterinary Physiology, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University , Musashinoi, Japan
                [3] 3Department of Molecular Carcinogenesis, Medical University of Łódź , Łódź, Poland
                [4] 4Fetal and Perinatal Pathology Unit, IRCCS Istituto “Giannina Gaslini” , Genoa, Italy
                [5] 5Department of Precision Medicine, University of Campania “Luigi Vanvitelli” , Naples, Italy
                [6] 6Telethon Institute of Genetics and Medicine (TIGEM) , Naples, Italy
                [7] 7Neuroradiology Unit, IRCCS Istituto “Giannina Gaslini” , Genoa, Italy
                [8] 8Fetal Medicine and Surgery Unit, IRCCS Istituto “Giannina Gaslini” , Genoa, Italy
                [9] 9Medical Genetics Unit, Maria Paternò Arezzo Hospital , Ragusa, Italy
                [10] 10Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini” , Genoa, Italy
                [11] 11Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa , Genoa, Italy
                [12] 12Department of Surgical Sciences and Integrated Diagnostics (DISC), Pathology Division of Anatomic Pathology, University of Genoa , Genoa, Italy
                [13] 13Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London , London, United Kingdom
                Author notes

                Edited by: David F. Clayton, Queen Mary University of London, United Kingdom

                Reviewed by: Martin W. Breuss, University of California, San Diego, United States; Michael John Gambello, Emory University, United States

                *Correspondence: Vincenzo Salpietro, v.salpietro@ 123456ucl.ac.uk

                These authors have contributed equally to this work

                This article was submitted to Neurogenomics, a section of the journal Frontiers in Neuroscience

                Copyright © 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.

                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 50, Pages: 11, Words: 0
                Brief Research Report

                wwox,woree syndrome,neuropathology,animal model,developing brain,cytoskeleton
                wwox, woree syndrome, neuropathology, animal model, developing brain, cytoskeleton


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