Epithelial geometry regulates spindle orientation and progenitor fate during formation of the mammalian epidermis

Abstract

The ability to control cell fate through oriented division is imperative for the proper development of many organs, such as the stratified epidermis. Basal progenitor cells of the mammalian epidermis orient their divisions parallel or perpendicular to the basement membrane to expand the stem cell pool or produce differentiated stratified layers. Although any given basal cell is capable of either division orientation, the mechanisms that regulate the choice between division orientations are unknown. Here, using time-lapse imaging to follow divisions and fates of basal progenitors, we investigate the role of planar cell polarity (PCP) and tissue architecture during epidermal stratification. We find that embryos defective for the core PCP gene, Vangl2, exhibit increased perpendicular, asymmetric divisions at the expense of planar, symmetric divisions, but surprisingly, this is not due to defective Vangl2 function in the epidermis. We link this reduction in planar divisions to alterations in cell geometry and packing, which are indirectly caused by the neural tube closure defects characteristic of planar cell polarity mutants. We demonstrate that early in epidermal stratification, there is a close relationship between cell density, interphase cell height-to-width aspect ratio, and mitotic spindle orientation. These data show that basal epidermal cells utilize packing and shape, rather than cortical PCP cues, to inform division orientation. We propose a model in which local tissue architecture regulates the decision between symmetric and stratifying divisions, a mechanism that allows flexibility for basal stem cells to adapt to the needs of the developing tissue.