Dia1 Coordinates Differentiation and Cell Sorting in a Stratified Epithelium

Abstract

Although implicated in adhesion, few studies address how actin assembly factors guide cell positioning in multicellular tissue. The formin, Dia1, localizes to the proliferative basal layer of epidermis. In organotypic cultures, Dia1 depletion reduced basal cell density and resulted in stratified tissue with disorganized differentiation and proliferative markers. Since crowding induces differentiation in epidermal tissue, we hypothesized that Dia1 allows cells to reach densities amenable to differentiation prior to stratification. Consistent with this hypothesis, forced crowding of Dia1-deficient cells rescued transcriptional abnormalities. Dia1 promotes rapid growth of lateral adhesions, a behavior consistent with the ability of cells to remain monolayered when crowded. In aggregation assays, cells sorted into distinct layers based on Dia1 expression status. These results suggested that as basal cells proliferate, reintegration and packing of Dia1-positive daughter cells is favored while Dia1-negative cells tend to delaminate to a suprabasal compartment. These data demonstrate how formin expression patterns play a crucial role in constructing distinct domains within stratified epithelia. SummaryHarmon et al demonstrate that differential expression of an actin nucleator, the formin, Dia1, drives cell sorting and maintains distinct morphological domains within an epithelial tissue. This illuminates the possible utility of evolving a large formin family in orchestrating the compartmentalization and differentiation of complex tissues.