During embryonic development, a single-layered ectodermal cell layer transforms into a multi- layered epidermis. The multi-layered or stratified architecture of the epidermis is essential for its barrier function - allowing it to prevent both dehydration and infection. Stratification of the epidermis is driven by asymmetric cell divisions that generate one proliferative basal cell and one suprabasal cell that expresses differentiation markers. We want to understand how epidermal cells reorient their mitotic spindle in order to divide asymmetrically. A necessary first step toward this goal is to define the dynamics of both spindle poles and microtubules during the process of spindle reorientation. We have developed the tools and methodologies to complete this analysis. On the molecular level, NuMA is a core component of the asymmetric cell division machinery. In invertebrates, it is required for asymmetric cell divisions, though how it is localized and what its function is remains undetermined. We will test the functional relevance of NuMA's protein-protein interactions in both its localization to the cell cortex and in spindle reorientation. The work proposed will have broad significance as asymmetric divisions play fundamental roles in cell-type diversification, stem cell homeostasis, morphogenesis and the immune response. Additionally, disruption of asymmetric divisions has been proposed to promote tumorigenesis. Therefore, understanding the mechanisms driving asymmetric cell division will provide insights not only into epidermal stratification but also additional physiological and pathological processes.
Stratification of the epidermis is a necessary step in the formation of the epidermal barrier. During development, stratification is driven by asymmetric cell divisions. Here we propose to examine the mechanism by which these divisions occur. These studies may shed light on or lead to treatments for conditions as diverse as lack of barrier function in premature infants, wound-healing, and cancer.
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