Skin-Specific Deletion of Mis18 alpha Impedes Proliferation and Stratification of Epidermal Keratinocytes

Abstract

The Mis18 proteins (Mis18 alpha, Mis18 beta, and M18BP1) are pivotal to the deposition of CENP-A at the centromere during cell cycle progression and are indispensable for embryonic development. Here, we show that Mis18 alpha is critical for the proliferation of keratinocytes and stratification of the epidermis. Mice lacking Mis18 alpha in the epidermis died shortly after birth, showing skin abnormalities like thin and translucent skin and defective skin barrier functions. The epidermis of newborn Mis18 alpha-deficient mice lacked distinct stratification and mature hair follicles, with a reduction in the number of proliferating cells and increased cell death in the basal layer. Earlier expression of the Cre recombinase from keratin-14 promoter in the ventral region resulted in earlier keratinocyte death in the ventral part compared with the dorsal part in the absence of Mis18 alpha, leading to more severe malformation of the ventral epidermal layers. As observed in Mis18 alpha-deficient mouse keratinocytes, knockdown of Mis18 alpha in HaCaT cells caused marked loss of centromeric CENP-A dots and chromosomal misalignment. Overall, we propose that Mis18 alpha is important for epidermal cell proliferation and stratification, because it is required for the deposition of CENP-A at the centromeric nucleosomes.