IRhom2 mutation leads to aberrant hair follicle differentiation in mice.

Yang Leilei,Wang Dongping,Liu Bing,Ye Huahu,Wang Shaoxia,Li Yang,Zhang Guangzhou,Zeng Lin,Xu Yuan,Li Wenlong,Peng Ruiyun,Shang Shichen,Andrzej T Slominski

doi:10.1371/journal.pone.0115114

Abstract

iRhom1 and iRhom2 are inactive homologues of rhomboid intramembrane serine proteases lacking essential catalytic residues, which are necessary for the maturation of TNFα-converting enzyme (TACE). In addition, iRhoms regulate epidermal growth factor family secretion. The functional significance of iRhom2 during mammalian development is largely unclear. We have identified a spontaneous single gene deletion mutation of iRhom2 in Uncv mice. The iRhom2Uncv/Uncv mice exhibit hairless phenotype in a BALB/c genetic background. In this study, we observed dysplasia hair follicles in iRhom2Uncv/Uncv mice from postnatal day 3. Further examination found decreased hair matrix proliferation and aberrant hair shaft and inner root sheath differentiation in iRhom2Uncv/Uncv mutant hair follicles. iRhom2 is required for the maturation of TACE. Our data demonstrate that iRhom2Uncv cannot induce the maturation of TACE in vitro and the level of mature TACE is also significantly reduced in the skin of iRhom2Uncv/Uncv mice. The activation of Notch1, a substrate of TACE, is disturbed, associated with dramatically down-regulation of Lef1 in iRhom2Uncv/Uncv hair follicle matrix. This study identifies iRhom2 as a novel regulator of hair shaft and inner root sheath differentiation.

Highlights

Introduction iRhom1 and iRhom2, which are inactive homologues of the rhomboid intramembrane serine proteases that lack the essential catalytic residues [1]. iRhom1 and iRhom2 regulate the secretion of the epidermal growth factor (EGF) family by endoplasmic reticulum-associated degradation [2]. iRhom2 is required for the release of tumor necrosis factor a (TNFa) in macrophages by controlling
This study suggests that iRhom2 regulates hair shaft and inner root sheath (IRS) differentiation by modulating Notch1 and Wnt signaling pathway which maybe mediated by TNFa-converting enzyme (TACE)
We discovered that iRhom2 regulate murine hair follicle differentiation by modulating Notch1 and Wnt signaling pathway which maybe mediated by TACE

Summary

Introduction

IRhom and iRhom, which are inactive homologues of the rhomboid intramembrane serine proteases that lack the essential catalytic residues [1]. iRhom and iRhom regulate the secretion of the epidermal growth factor (EGF) family by endoplasmic reticulum-associated degradation [2]. iRhom is required for the release of tumor necrosis factor a (TNFa) in macrophages by controllingPLOS ONE | DOI:10.1371/journal.pone.0115114 December 29, 2014iRhom in Follicle Differentiation the maturation of TNFa-converting enzyme (TACE, called ADAM17) [3,4,5]. IRhom and iRhom regulate the secretion of the epidermal growth factor (EGF) family by endoplasmic reticulum-associated degradation [2]. IRhom is required for the release of tumor necrosis factor a (TNFa) in macrophages by controlling. IRhom in Follicle Differentiation the maturation of TNFa-converting enzyme (TACE, called ADAM17) [3,4,5]. IRhom controls the activation and substrate selectivity of TACEdependent shedding events [6]. Dominant mutations of iRhom is the cause of human tylosis esophageal cancer [7, 8]. IRhom plays an important role in inflammatory arthritis [9]. IRhom knockout mice could survive in a lethal lipopolysaccharide dose [5]. The functional significance of iRhom during mammalian skin development is unclear

Methods

Results

Conclusion