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

Ying-Tsen Chou,Nan-Shan Chang,Feng-Jie Lai,Li-Jin Hsu

doi:10.3389/fcell.2020.558432

Abstract

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.

Highlights

WW domain-containing oxidoreductase (WWOX) has been initially known as a proapoptotic tumor suppressor (Chang et al, 2007; Lo et al, 2015; Schrock and Huebner, 2015)
When assessing the skin barrier function, we did not find increased transepidermal water loss in Wwox−/− mice as the lipid layer was still maintained on the Wwox−/− epidermal surface (Supplementary Figure S1)
The Wwox−/− epidermal thickness was significantly decreased at postnatal day (P) 21 (Figures 1B,D)

Summary

Introduction

WW domain-containing oxidoreductase (WWOX) has been initially known as a proapoptotic tumor suppressor (Chang et al, 2007; Lo et al, 2015; Schrock and Huebner, 2015). Ser phosphorylation and accumulation of WWOX protein in the brain contribute to the Alzheimer’s memory loss in mice (Chang et al, 2015; Lee et al, 2017). WWOX controls many biological functions, including bubbling cell death and genomic stability (Abu-Remaileh et al, 2015; Chen et al, 2015), suggesting that WWOX plays an important role in normal cellular/physiological homeostasis maintenance. The first WW domain of WWOX participates in protein-protein interactions in multiple signaling pathways (Abu-Odeh et al, 2014; Liu et al, 2018; Saigo et al, 2018). Crosstalk of WWOX with many signal pathways implies the involvement of WWOX in development and stemness maintenance (Chen et al, 2019)

Methods

Results

Discussion

Conclusion