Pannexin 3 regulates skin development via Epiprofin

Peipei Zhang,Andrew Doyle,Bing He,Masaki Ishikawa,Yoshihiko Yamada,Takashi Nakamura

doi:10.1038/s41598-021-81074-1

Abstract

Pannexin 3 (Panx3), a member of the gap junction pannexin family is required for the development of hard tissues including bone, cartilage and teeth. However, the role of Panx3 in skin development remains unclear. Here, we demonstrate that Panx3 regulates skin development by modulating the transcription factor, Epiprofin (Epfn). Panx3−/− mice have impaired skin development and delayed hair follicle regeneration. Loss of Panx3 in knockout mice and suppression by shRNA both elicited a reduction of Epfn expression in the epidermis. In cell culture, Panx3 overexpression promoted HaCaT cell differentiation, cell cycle exit and enhanced Epfn expression. Epfn−/− mice and inhibition of Epfn by siRNA showed no obvious differences of Panx3 expression. Furthermore, Panx3 promotes Akt/NFAT signaling pathway in keratinocyte differentiation by both Panx3 ATP releasing channel and ER Ca2+ channel functions. Our results reveal that Panx3 has a key role factor for the skin development by regulating Epfn.

Highlights

Pannexin 3 (Panx3), a member of the gap junction pannexin family is required for the development of hard tissues including bone, cartilage and teeth
Further examination revealed Panx3−/− mice showed no obvious difference in the first hair cycle and no premature hair follicle anagen cessation, hair loss, or hair thinning commonly associated with severe malnutrition (Fig. 1A, postborn day 4 (P4) and P10)
ShPanx[3] reduced Panx[3] and differentiation marker, Notch[1] expression in keratinocyte media (KM) + Ca2+ condition (Supplementary Fig. 5B). These results indicate that Panx[3] regulates Epfn expression during keratinocyte differentiation

Summary

Introduction

Pannexin 3 (Panx3), a member of the gap junction pannexin family is required for the development of hard tissues including bone, cartilage and teeth. Panx[3] promotes Akt/ NFAT signaling pathway in keratinocyte differentiation by both Panx[3] ATP releasing channel and ER Ca2+ channel functions. Panx[3] releases intracellular ATP into the extracellular space, to activate PI3K/ Akt pathway This phosphorylation of Akt initiates endoplasmic reticulum (ER)-associated Panx[3] to increase intracellular Ca2+ levels, which upregulates the calmodulin/calcineurin/NFAT signaling pathway to promote differentiation[11,14,18]. In HaCaT cells, Panx[3] overexpression increases Epfn expression and keratinocyte differentiation, while shRNA ablation of Panx[3] decreases the presence of Epfn. Panx[3] promotes keratinocyte differentiation via Epfn signaling through the activation of Akt/NFAT signaling by its ATP releasing channel and ER Ca2+ channel functions

Methods

Results

Conclusion