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

Cheng, Ya-Yun; Chou, Yi‐Chieh; Lai, Feng‐Jie; Jan, Ming‐Shiou; Chang, Tong‐Bou; Jou, I‐Ming; Chen, Pei-Shiuan; Lo, Jui-Yen; Huang, Shiang‐Suo; Chang, Nan‐Shan; Liou, Yung-Tsai; Hsu, Po-Yang; Cheng, Hui-Ching; Lin, Yee‐Shin; Hsu, Li Jin

doi:10.1186/s40478-020-0883-3

Cited by 36 publications

(63 citation statements)

References 65 publications

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“…To investigate whether WWOX deficiency affects skin development, homeostasis and functions, whole-body knockout mouse models for Wwox gene were used in this study (Cheng et al, 2020). The absence of WWOX protein expression in Wwox −/− mouse skin was verified ( Figure 1A).…”

Section: Wwox Loss Results In Reduced Epidermal Integritymentioning

confidence: 97%

“…Whole-body Wwox gene knockout mice were generated as described previously (Tsai et al, 2013;Cheng et al, 2020). This study was carried out in accordance with the approved protocols for animal use from the Institutional Animal Care and Use Committee of National Cheng Kung University.…”

Section: Animals and Cell Culturementioning

confidence: 99%

“…Semithin sections (0.5 µm) were stained with 1% toluidine blue/2% sodium borate for 2 min, washed with distilled water and examine under a light microscope (Olympus BX51, Tokyo, Japan). Ultrathin sections (90 nm) were prepared, stained with 2% uranyl acetate for 20 min and 4% lead citrate for 3 min, and examined under a transmission electron microscope (JEOL JEM-1200EX, Tokyo, Japan) as described previously (Cheng et al, 2020).…”

Section: Toluidine Blue Staining and Transmission Electron Microscopymentioning

confidence: 99%

“…Previous studies have demonstrated that lipid metabolism, steroidogenesis, bone development and metabolism, and central nervous system are defective in Wwox −/− mice (Aqeilan et al, 2008;Aqeilan et al, 2009;Hussain et al, 2019;Cheng et al, 2020). The deficits in whole-body Wwox knockout mice may recapitulate the crucial clinical features of human pathological conditions (Cheng et al, 2020). However, the main cause leading to early death of WWOX-deficient newborns is still unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Wwox knockout (Wwox −/− ) mice display similar symptoms and die within 4 weeks after birth (Aqeilan et al, 2007;Ludes-Meyers et al, 2009). Previous studies have demonstrated that lipid metabolism, steroidogenesis, bone development and metabolism, and central nervous system are defective in Wwox −/− mice (Aqeilan et al, 2008;Aqeilan et al, 2009;Hussain et al, 2019;Cheng et al, 2020). The deficits in whole-body Wwox knockout mice may recapitulate the crucial clinical features of human pathological conditions (Cheng et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Chou

Lai

Chang

et al. 2020

Front. Cell Dev. Biol.

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Deficiency of tumor suppressor WW domain-containing oxidoreductase (WWOX) in humans and animals leads to growth retardation and premature death during postnatal developmental stages. Skin integrity is essential for organism survival due to its protection against dehydration and hypothermia. Our previous report demonstrated that human epidermal suprabasal cells express WWOX protein, and the expression is gradually increased toward the superficial differentiated cells prior to cornification. Here, we investigated whether abnormal skin development and homeostasis occur under Wwox deficiency that may correlate with early death. We determined that keratinocyte proliferation and differentiation were decreased, while apoptosis was increased in Wwox −/− mouse epidermis and primary keratinocyte cultures and WWOX-knockdown human HaCaT cells. Without WWOX, progenitor cells in hair follicle junctional zone underwent massive proliferation in early postnatal developmental stages and the stem/progenitor cell pools were depleted at postnatal day 21. These events lead to significantly decreased epidermal thickness, dehydration state, and delayed hair development in Wwox −/− mouse skin, which is associated with downregulation of prosurvival MEK/ERK signaling in Wwox −/− keratinocytes. Moreover, Wwox depletion results in substantial downregulation of dermal collagen contents in mice. Notably, Wwox −/− mice exhibit severe loss of subcutaneous adipose tissue and significant hypothermia. Collectively, our knockout mouse model supports the validity of WWOX in assisting epidermal and adipose homeostasis, and the involvement of prosurvival ERK pathway in the homeostatic responses regulated by WWOX.

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Section: Wwox Loss Results In Reduced Epidermal Integritymentioning

confidence: 97%

Section: Animals and Cell Culturementioning

confidence: 99%

Section: Toluidine Blue Staining and Transmission Electron Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Chou

Lai

Chang

et al. 2020

Front. Cell Dev. Biol.

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Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Chong

Cao

Fung

et al. 2022

American J of Med Genetics Pt A

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WWOX biallelic loss‐of‐function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX‐related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

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Loss of fragile WWOX gene leads to senescence escape and genome instability

Cheng,

Huang,

Lai

et al. 2023

Cell. Mol. Life Sci.

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Induction of DNA damage response (DDR) to ensure accurate duplication of genetic information is crucial for maintaining genome integrity during DNA replication. Cellular senescence is a DDR mechanism that prevents the proliferation of cells with damaged DNA to avoid mitotic anomalies and inheritance of the damage over cell generations. Human WWOX gene resides within a common fragile site FRA16D that is preferentially prone to form breaks on metaphase chromosome upon replication stress. We report here that primary Wwox knockout (Wwox−/−) mouse embryonic fibroblasts (MEFs) and WWOX-knockdown human dermal fibroblasts failed to undergo replication-induced cellular senescence after multiple passages in vitro. Strikingly, by greater than 20 passages, accelerated cell cycle progression and increased apoptosis occurred in these late-passage Wwox−/− MEFs. These cells exhibited γH2AX upregulation and microsatellite instability, indicating massive accumulation of nuclear DNA lesions. Ultraviolet radiation-induced premature senescence was also blocked by WWOX knockdown in human HEK293T cells. Mechanistically, overproduction of cytosolic reactive oxygen species caused p16Ink4a promoter hypermethylation, aberrant p53/p21Cip1/Waf1 signaling axis and accelerated p27Kip1 protein degradation, thereby leading to the failure of senescence induction in Wwox-deficient cells after serial passage in culture. We determined that significantly reduced protein stability or loss-of-function A135P/V213G mutations in the DNA-binding domain of p53 caused defective induction of p21Cip1/Waf1 in late-passage Wwox−/− MEFs. Treatment of N-acetyl-l-cysteine prevented downregulation of cyclin-dependent kinase inhibitors and induced senescence in Wwox−/− MEFs. Our findings support an important role for fragile WWOX gene in inducing cellular senescence for maintaining genome integrity during DDR through alleviating oxidative stress.

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

Cited by 36 publications

References 65 publications

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Loss of fragile WWOX gene leads to senescence escape and genome instability

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