The WWOX Gene Influences Cellular Pathways in the Neuronal Differentiation of Human Neural Progenitor Cells

Kośla, Katarzyna; Płuciennik, Elżbieta; Styczeń-Binkowska, Ewa; Nowakowska, Magdalena; Orzechowska, Magdalena

doi:10.3389/fncel.2019.00391

Cited by 11 publications

(15 citation statements)

References 73 publications

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“…Neuronal cell apoptosis was observed in the brain tissues of Wwox −/− mice (Additional file 1: Figure S9). Together, in agreement with a recent study using a human neural progenitor cell culture system [34], our results indicate that loss of Wwox causes disorders in neuronal migration and development and brain malformations in mice.…”

Section: Wwox Is Required For Proper Neuronal Migration and Developmentsupporting

confidence: 92%

“…WWOX has been shown to be highly expressed in the secretory epithelial cells of hormonally regulated organs including breast, ovary, testis and prostate, and targeted deletion of Wwox in mouse mammary gland leads to impaired mammary ductal development [1,53]. WWOX expression is relatively strong in human, rat and mouse neural tissues, and varies according to the location [19,34,53,61]. Notably, WWOX may interact with steroid hormone 17β-estradiol via its NSYK (Asn-Ser-Tyr-Lys) motif in the C-terminal short-chain alcohol dehydrogenase/reductase domain for neuroprotection [42].…”

Section: Discussionmentioning

confidence: 99%

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Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Cheng

Chou

Lai

et al. 2020

acta neuropathol commun

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Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox −/− mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox −/− mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine-and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3β (GSK3β) occurs in Wwox −/− mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3β by lithium ion significantly abolishes the onset of PTZinduced seizure in Wwox −/− mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3β with lithium ion ameliorates epilepsy.

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Section: Wwox Is Required For Proper Neuronal Migration and Developmentsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Cheng

Chou

Lai

et al. 2020

acta neuropathol commun

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“…In addition, cerebral cortex PAS-stain revealed irregular migration trajectories of glial cells, known to be important in the guidance of migrating neurons. Interestingly, it has been previously showed by some of us (KK, AKB) that Wwox silencing in neural progenitor cells may alter the expression of a large number of genes (e.g., DCLK, NEFM, and NEFL) involved in neurofilament assembly, cytoskeleton organization and chromatin remodeling (Kośla et al, 2019). In the present study, we performed detailed analysis of gene expression of Wwox-depleted neural progenitors and differentiated post-mitotic neurons.…”

Section: Discussionmentioning

confidence: 81%

“…To analyze the transcriptomic changes caused by WWOX depletion in human neuronal progenitor cells (hNPC), and their putative connection to observed disease phenotypes, we employed the data (deposited in GEO Database with accession number GSE126075), obtained in the experiment of in vitro WWOX silencing in H9-derived hNPC as previously described by some of us (Kośla et al, 2019). WWOX was silenced by a shRNA lentiviral delivery system and the transcriptome was analyzed by CAGE (cap analysis of gene expression) method.…”

Section: Transcriptomic Analyses Of Hnpc and Neurons With Silenced Wwoxmentioning

confidence: 99%

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

et al. 2020

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“…Consistently, neuronal progenitor cells with silenced WWOX showed enhanced adhesion to extracellular matrix proteins, downregulation of MMP2/9 expression, and impaired 3D growth. 48 Recently, it has been reported that WWOX knock out in mice indeed cause a disruption of neuronal migration in developing cerebral cortex, hippocampus, and cerebellum. Neuronal migration disorders in KO mice result in foliation impairment and brain malformation.…”

Section: Encephalopathymentioning

confidence: 99%

The WWOX gene in brain development and pathology

Kośla

Kałuzińska

2020

Exp Biol Med (Maywood)

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Shortly after its discovery in 2000, WWOX was hailed as a tumor suppressor gene. In subsequent years of research, this function was confirmed indisputably. Majority of tumors show high rate of loss of heterozygosity and decreased expression of WWOX. Nevertheless, over the years, the range of its known functions, at the cellular, organ and system levels, has expanded to include metabolism and endocrine system control and CNS differentiation and functioning. Despite of its function as a tumor suppressor gene, WWOX genetic alternations were found in a number of metabolic and neural diseases. A lack of WWOX protein as a consequence of germline mutations results in brain development disturbances and malfunctions. Impact statement WW domain-containing oxidoreductase encoded by the WWOX gene is a transcription regulator and a key player in a number of cellular and biological processes such as tumor suppression, cell proliferation, apoptosis induction, steroid metabolism, and central nervous system development. This review provides a comprehensive summary of currently known roles and discusses the importance of WWOX gene for CNS development and functioning.

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The WWOX Gene Influences Cellular Pathways in the Neuronal Differentiation of Human Neural Progenitor Cells

Cited by 11 publications

References 73 publications

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

The WWOX gene in brain development and pathology

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