Hemidesmosomes regulate epidermal differentiation during embryogenesis
In skin epidermis, integrins mediate adhesion of basal keratinocytes to the underlying basement membrane. While high expression of integrins has been correlated with stemness, there is limited direct evidence that integrins mediate keratinocyte retention within the basal layer. Here, we generate mosaic, epidermal-specific loss of integrin-{beta}4 (encoded by Itgb4) or its ligand, laminin-3{beta}3{gamma}2 (Lama3), using an in utero lentiviral-mediated approach. Although mutations in these genes cause postnatal skin blistering in mice and humans, we observe no evidence of epidermal-dermal separation embryonically. Despite no weobvious alterations to apicobasal polarity, Itgb4-deficient basal cells show mild defects in oriented cell divisions, with increased oblique divisions and altered telophase correction. However, differentiation via cellular delamination--where basal keratinocytes lose adhesion to the underlying basement membrane and transit into the suprabasal layer--is elevated upon Itgb4 and Lama3 loss. Notably, hyperactive Notch signaling both decreases integrin-{beta}4 expression and increases delamination. These findings conclusively demonstrate a causal role for hemidesmosomes in regulating epidermal differentiation through both mitotic and non-mitotic mechanisms and shed additional light on the programs regulating delamination. HighlightsO_LIEmbryonic loss of integrin-{beta}4 impairs hemidesmosome maturation, but does not cause blistering in the embryonic epidermis C_LIO_LIIntegrin-{beta}4 is dispensable for keratinocyte polarity but promotes telophase correction C_LIO_LIHemidesmosome adhesions regulate differentiation through delamination C_LI Summary StatementHemidesmosomes are specialized integrin complexes that anchor the epidermis to the basement membrane. We show that hemidesmosomal integrin-6{beta}4 and laminin-3{beta}3{gamma}2 regulate epidermal differentiation by promoting basal cell retention in embryogenesis.