MTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation

Xiaolei Ding,Maria Leptin,Sandra Iden,Markus A Rüegg,Sabine A Eming,Linda Partridge,Wilhelm Bloch,Michael N Hall

doi:10.1038/ncomms13226

Abstract

Mammalian target of rapamycin (mTOR), a regulator of growth in many tissues, mediates its activity through two multiprotein complexes, mTORC1 or mTORC2. The role of mTOR signalling in skin morphogenesis and epidermal development is unknown. Here we identify mTOR as an essential regulator in skin morphogenesis by epidermis-specific deletion of Mtor in mice (mTOREKO). mTOREKO mutants are viable, but die shortly after birth due to deficits primarily during the early epidermal differentiation programme and lack of a protective barrier development. Epidermis-specific loss of Raptor, which encodes an essential component of mTORC1, confers the same skin phenotype as seen in mTOREKO mutants. In contrast, newborns with an epidermal deficiency of Rictor, an essential component of mTORC2, survive despite a hypoplastic epidermis and disruption in late stage terminal differentiation. These findings highlight a fundamental role for mTOR in epidermal morphogenesis that is regulated by distinct functions for mTORC1 and mTORC2.

Highlights

Mammalian target of rapamycin, a regulator of growth in many tissues, mediates its activity through two multiprotein complexes, mTORC1 or mTORC2
Multiple upstream signals regulate the mTOR pathway, including the ‘classical’ mTOR regulators, such as the receptor tyrosine kinasePI3K-Akt signalling cascade[10,11], and the more recently described inputs from keratin 17 or the Wnt and Notch pathways[12,13,14,15]. These pathways are critical in epidermal morphogenesis, and we hypothesized that mTOR might serve a role in skin development and epidermal barrier formation
We have shown that mTOR signalling is essential for proper skin morphogenesis and for the development of a protective epidermal barrier

Summary

Introduction

Mammalian target of rapamycin (mTOR), a regulator of growth in many tissues, mediates its activity through two multiprotein complexes, mTORC1 or mTORC2. Newborns with an epidermal deficiency of Rictor, an essential component of mTORC2, survive despite a hypoplastic epidermis and disruption in late stage terminal differentiation These findings highlight a fundamental role for mTOR in epidermal morphogenesis that is regulated by distinct functions for mTORC1 and mTORC2. Multiple upstream signals regulate the mTOR pathway, including the ‘classical’ mTOR regulators, such as the receptor tyrosine kinasePI3K-Akt signalling cascade[10,11], and the more recently described inputs from keratin 17 or the Wnt and Notch pathways[12,13,14,15] These pathways are critical in epidermal morphogenesis, and we hypothesized that mTOR might serve a role in skin development and epidermal barrier formation. Whereas mTOR inhibitors appear to be tolerated by healthy skin, wound complications are one of the most frequent side-effects of mTOR-inhibitors used in the clinic and can lead to therapy interruption[31]

Methods

Results

Conclusion