Hair Follicular Expression and Function of Group X Secreted Phospholipase A2 in Mouse Skin

Kei Yamamoto,Yoshimi Miki,Yoshikazu Ishimoto,Kazutaka Ikeda,Kiyoko Fukami,Yasumasa Nishito,Hiroki Nakanishi,Ryo Taguchi,Yukio Ishikawa,Yuki Isogai,Kohji Hanasaki,Noriko Suzuki,Toshiharu Ishii,Tetsuyuki Kobayashi,Makoto Murakami,Hiroyasu Sato,Yoshitaka Taketomi,Shiro Masuda ,Yusuke Yokota ,Kazuyuki Morioka

doi:10.1074/jbc.m110.206714

Abstract

Although perturbed lipid metabolism can often lead to skin abnormality, the role of phospholipase A(2) (PLA(2)) in skin homeostasis is poorly understood. In the present study we found that group X-secreted PLA(2) (sPLA(2)-X) was expressed in the outermost epithelium of hair follicles in synchrony with the anagen phase of hair cycling. Transgenic mice overexpressing sPLA(2)-X (PLA2G10-Tg) displayed alopecia, which was accompanied by hair follicle distortion with reduced expression of genes related to hair development, during a postnatal hair cycle. Additionally, the epidermis and sebaceous glands of PLA2G10-Tg skin were hyperplasic. Proteolytic activation of sPLA(2)-X in PLA2G10-Tg skin was accompanied by preferential hydrolysis of phosphatidylethanolamine species with polyunsaturated fatty acids as well as elevated production of some if not all eicosanoids. Importantly, the skin of Pla2g10-deficient mice had abnormal hair follicles with noticeable reduction in a subset of hair genes, a hypoplasic outer root sheath, a reduced number of melanin granules, and unexpected up-regulation of prostanoid synthesis. Collectively, our study highlights the spatiotemporal expression of sPLA(2)-X in hair follicles, the presence of skin-specific machinery leading to sPLA(2)-X activation, a functional link of sPLA(2)-X with hair follicle homeostasis, and compartmentalization of the prostanoid pathway in hair follicles and epidermis.

Highlights

Perturbed lipid metabolism can often lead to skin abnormality, the role of phospholipase A2 (PLA2) in skin homeostasis is poorly understood
We found that Tg overexpression of secreted PLA2s (sPLA2s)-X in mice resulted in skin abnormalities characterized by alopecia, unusual hair cycling, and epidermal and sebaceous gland hyperplasia, accompanied by aberrant hydrolysis of phosphatidylethanolamine (PE) and increased synthesis of some eicosanoids
Because the severe skin abnormalities in PLA2G10-Tg mice were evident during P15-P30, in subsequent studies we focused on detailed phenotypic analyses of Tg mouse skin at this early stage

Summary

Introduction

Perturbed lipid metabolism can often lead to skin abnormality, the role of phospholipase A2 (PLA2) in skin homeostasis is poorly understood. In line with the hairless phenotype of PLA2G10-Tg mice, quantitative RT-PCR revealed markedly reduced expression of a subset of genes related to hair follicle differentiation and hair shaft formation, such as Shh (Sonic Hedgehog) and Bmp4 (bone morphogenetic protein 4), which regulate the proliferation and differentiation of matrix cells in the dermal papilla, and Msx2, Lef1, Foxn1, and Gata3, which are transcription factors required for proper differentiation of the hair shaft or IRS [1,2,3] (Fig. 2B).

Results

Conclusion