Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

Iacomino, Michele; Baldassari, Sımona; Tochigi, Yuki; Kośla, Katarzyna; Buffelli, Francesca; Torella, Annalaura; Severino, Mariasavina; Paladini, D.; Mandarà, Luana; Riva, Antonella; Scala, Marcello; Balagura, Ganna; Accogli, Andrea; Nigro, Vincenzo; Minetti, Carlo; Fulcheri, Ezio; Zara, Federico; Striano, Pasquale; Suzuki, Hiroyoshi; Salpietro, Vincenzo

doi:10.3389/fnins.2020.00644

Cited by 26 publications

(37 citation statements)

References 46 publications

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“…In agreement with our findings, a recent study that examined the brain histology of a fetus suffering from the WOREE syndrome reported anomalous migration of the external granular layer within the molecular layer of the cortex, a phenotype that was validated also in a rat model with spontaneous WWOX mutations (Iacomino et al , 2020 ). This observation is further supported by the transcriptomic analysis performed by Kosla et al ( 2019 ) on human neuronal progenitor cells (hNPCs) after silencing WWOX using shRNA.…”

Section: Discussionsupporting

confidence: 92%

“…The authors also reported decreased mitochondrial redox potential, enhanced cellular adhesion to the growth surface, and reduced expression of MMP2 and MMP9. Iacomino et al ( 2020 ) reanalyzed this transcriptomic data, focusing on genes associated with neuronal migration and differentiation, and found reduced expression of some neural migration‐related genes, such as microtubule proteins and kinesin family proteins. Notably, cortical layering was found to be affected by the status of the Wnt pathway (Qian et al , 2020 ), a pathway in which WWOX has been implicated through its binding partners.…”

Section: Discussionmentioning

confidence: 99%

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Modeling genetic epileptic encephalopathies using brain organoids

et al. 2021

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Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain‐containing oxidoreductase (WWOX) are associated with a relatively mild autosomal recessive spinocerebellar ataxia‐12 (SCAR12) and a more severe early infantile WWOX‐related epileptic encephalopathy (WOREE). In this study, we generated an in vitro model for DEEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR‐engineered human ES cells and from patient‐derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt pathway and DNA damage response impairment. Furthermore, we provide a proof of concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Modeling genetic epileptic encephalopathies using brain organoids

et al. 2021

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“…Hypomyelination with atrophy of the optic tract and cerebellar foliar white matter were also observed [ 38 ]. Interestingly, some of these observations agree with a recent report describing neuronal disorganization with defective architecture of the granular and molecular cell layers of cerebral cortex in brain histology samples from a WWOX null human fetus [ 39 ].…”

Section: Wwox-associated Cns Disorderssupporting

confidence: 91%

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Aldaz

Hussain

2020

IJMS

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The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.

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“…Transcriptional analysis of neurospheres derived from WWOX KO neural stem cells reveals alterations in the expression of genes related to neurological disorders, CNS development, and epilepsy [ 41 ]. Furthermore, transcriptomic analysis in WWOX-depleted human neural progenitor cells demonstrates that WWOX downregulation significantly alters the expression of genes involved in neuron migration and cytoskeleton organization [ 20 , 42 ]. Despite these studies, it is evident that detailed studies uncovering the molecular and cellular roles of WWOX in pediatric epilepsy are still lacking.…”

Section: Modeling Wwox Deficiency In Rodents Reveals An Epileptic Phenotypementioning

confidence: 99%

Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview

Banne

Abudiab

Abu-Swai

et al. 2021

Cells

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The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients). Individuals with these syndromes present with a highly heterogenous clinical spectrum, the most common clinical symptoms being severe epileptic encephalopathy and profound global developmental delay. Knowledge of the underlying pathophysiology of these syndromes, the range of variants of the WWOX gene and its genotype-phenotype correlations is limited, hampering therapeutic efforts. Therefore, there is a critical need to identify and consolidate all the reported variants in WWOX to distinguish between disease-causing alleles and their associated severity, and benign variants, with the aim of improving diagnosis and increasing therapeutic efforts. Here, we provide a comprehensive review of the literature on WWOX, and analyze the pathogenic variants from published and unpublished reports by collecting entries from the ClinVar, DECIPHER, VarSome, and PubMed databases to generate the largest dataset of WWOX pathogenic variants. We estimate the correlation between variant type and patient phenotype, and delineate the impact of each variant, and used GnomAD to cross reference these variants found in the general population. From these searches, we generated the largest published cohort of WWOX individuals. We conclude with a discussion on potential personalized medicine approaches to tackle the devastating disorders associated with WWOX mutations.

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Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

Abstract: We acknowledge the support from Enea-Eroi in ricerca onlus (www.eneaonlus.org). We also gratefully acknowledge the family for their participation to this study.

Cited by 26 publications

References 46 publications

Modeling genetic epileptic encephalopathies using brain organoids

Modeling genetic epileptic encephalopathies using brain organoids

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview

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