Frontiers in Neuroscience (Jun 2020)
Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development
- Michele Iacomino,
- Simona Baldassari,
- Yuki Tochigi,
- Katarzyna Kośla,
- Francesca Buffelli,
- Annalaura Torella,
- Annalaura Torella,
- Mariasavina Severino,
- Dario Paladini,
- Luana Mandarà,
- Antonella Riva,
- Marcello Scala,
- Marcello Scala,
- Ganna Balagura,
- Ganna Balagura,
- Andrea Accogli,
- Andrea Accogli,
- Vincenzo Nigro,
- Vincenzo Nigro,
- Carlo Minetti,
- Carlo Minetti,
- Ezio Fulcheri,
- Ezio Fulcheri,
- Federico Zara,
- Federico Zara,
- Andrzej K. Bednarek,
- Pasquale Striano,
- Pasquale Striano,
- Hiroetsu Suzuki,
- Vincenzo Salpietro,
- Vincenzo Salpietro,
- Vincenzo Salpietro
Affiliations
- Michele Iacomino
- Unit of Medical Genetics, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Simona Baldassari
- Unit of Medical Genetics, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Yuki Tochigi
- Laboratory of Veterinary Physiology, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashinoi, Japan
- Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Łódź, Łódź, Poland
- Francesca Buffelli
- Fetal and Perinatal Pathology Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Annalaura Torella
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
- Annalaura Torella
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Mariasavina Severino
- Neuroradiology Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Dario Paladini
- Fetal Medicine and Surgery Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Luana Mandarà
- Medical Genetics Unit, Maria Paternò Arezzo Hospital, Ragusa, Italy
- Antonella Riva
- 0Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Marcello Scala
- 0Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Marcello Scala
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Ganna Balagura
- 0Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Ganna Balagura
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Andrea Accogli
- Unit of Medical Genetics, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Andrea Accogli
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Vincenzo Nigro
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
- Vincenzo Nigro
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- Carlo Minetti
- 0Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Carlo Minetti
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Ezio Fulcheri
- Fetal and Perinatal Pathology Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Ezio Fulcheri
- 2Department of Surgical Sciences and Integrated Diagnostics (DISC), Pathology Division of Anatomic Pathology, University of Genoa, Genoa, Italy
- Federico Zara
- Unit of Medical Genetics, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Federico Zara
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Andrzej K. Bednarek
- Department of Molecular Carcinogenesis, Medical University of Łódź, Łódź, Poland
- Pasquale Striano
- 0Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Pasquale Striano
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Hiroetsu Suzuki
- Laboratory of Veterinary Physiology, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashinoi, Japan
- Vincenzo Salpietro
- 0Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”, Genoa, Italy
- Vincenzo Salpietro
- 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
- Vincenzo Salpietro
- 3Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, United Kingdom
- DOI
- https://doi.org/10.3389/fnins.2020.00644
- Journal volume & issue
-
Vol. 14
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.
Keywords
