Asymmetric cell divisions promote stratification and differentiation of mammalian skin

Abstract

To perform its function as an effective physical barrier our skin forms several layers of epidermal cells that are continually renewed. How this process occurs has been unclear, but previous studies in cultured skin cells suggested that stem cells at the base of the epidermis form new cells that migrate outwards to the skin surface. Work on mouse embryos now shows that the parent stem cells anchored at the base of the epidermis have the novel ability to replicate asymmetrically. They generate a ‘suprabasal’ cell, packed with integrins and growth factors, that stays put and above it a proliferative basal cell primed for differentiation and migration. The epidermis is a stratified squamous epithelium forming the barrier that excludes harmful microbes and retains body fluids. To perform these functions, proliferative basal cells in the innermost layer periodically detach from an underlying basement membrane of extracellular matrix, move outward and eventually die. Once suprabasal, cells stop dividing and enter a differentiation programme to form the barrier1. The mechanism of stratification is poorly understood. Although studies in vitro have led to the view that stratification occurs through the delamination and subsequent movement of epidermal cells2,3,4, most culture conditions favour keratinocytes that lack the polarity and cuboidal morphology of basal keratinocytes in tissue. These features could be important in considering an alternative mechanism, that stratification occurs through asymmetric cell divisions in which the mitotic spindle orients perpendicularly to the basement membrane5,6,7. Here we show that basal epidermal cells use their polarity to divide asymmetrically, generating a committed suprabasal cell and a proliferative basal cell. We further demonstrate that integrins and cadherins are essential for the apical localization of atypical protein kinase C, the Par3–LGN–Inscuteable complex and NuMA–dynactin to align the spindle.