Gsdma3 regulates hair follicle differentiation via Wnt5a-mediated non-canonical Wnt signaling pathway.

Long He,Yuhong Li,Chunyan Hu,Yizhan Xing,Mingxing Lei,Li Yang,Xiaohua Lian,Wanqian Liu,Tian Yang,Peixing Chen

doi:10.18632/oncotarget.22212

Long He, Yuhong Li + Show 8 more

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https://doi.org/10.18632/oncotarget.22212

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Abstract

Hair follicle is a mini-organ that consists of complex but well-organized structures, which are differentiated from hair follicle progenitor or stem cells. How non-canonical Wnt signaling pathway is involved in regulating hair follicle differentiation remains elusive. Here we showed that Wnt5a regulates hair follicle differentiation through an epithelial-mesenchymal interaction mechanism in mice. We first observed that Wnt5a is expressed in the epithelial and dermal papilla cells during hair follicle development and growth. For the upstream of Wnt5a, RT-PCR and immunohistochemistry staining showed that Wnt5a expression is significantly decreased in the Gsdma3-mutant mice in vivo. Overexpression of Gsdma3 results in a significantly increased expression of Wnt5a in the cultured epidermal cells in vitro. We also checked the downstream factors of Wnt5a by adenovirus-mediated overexpression of Wnt5a to the dermal papilla cells isolated from the mouse whisker. We found that overexpression of Wnt5a suppresses canonical Wnt signaling pathway effectors such as β-catenin and Lef1. In addition, genes involved in maintaining cell quiescent state are also significantly decreased in their expression to the DP cells which were treated by Wnt5a. Our study indicates that Wnt5a mediates epithelia-expressed Gsdma3 to influence DP cell behaviors, which in turn regulate hair follicle epithelia differentiation in mice.

Highlights

Ectodermal organs consist of two important cellular partitions including epithelium and mesenchyme, which develop from different germ layers during early developmental stages but influence each other by direct cell-cell interactions or paracrine factors such as growth factors and extracellular matrix [1]
When hair follicle enters full anagen at postnatal day 8 (P8), immunohistochemistry staining shows that Wnt5a is expressed at a high level in the inner root sheath (IRS), and a lower level in the outer root sheath (ORS), dermal papilla (DP) and hair matrix (Figure 1D)
Increasing evidence shows that non-canonical wingless-type MMTV integration site family (Wnt) signaling pathway is critical for hair follicle development, growth and regeneration

Summary

Introduction

Ectodermal organs consist of two important cellular partitions including epithelium and mesenchyme, which develop from different germ layers during early developmental stages but influence each other by direct cell-cell interactions or paracrine factors such as growth factors and extracellular matrix [1]. Hair follicle positions as a consummate and highly tractable model to study epithelialmesenchymal interactions. It includes both epithelial tissues and a group of specified mesenchymal cells known as dermal papilla (DP) [2]. Epithelial-mesenchymal interactions play roles in most development, growth and regeneration stages of hair follicle, to coordinate the formation of complex cellular components and structures of the follicle. Hair follicle undergoes cyclic growth consisting of anagen, catagen and telogen phases [4,5,6]

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