Regulation of asymmetric cell division in the epidermis

Asymmetric cell divisions (ACDs) generate cellular diversity during the development of multi-cellular organisms from a single-celled embryo. The asymmetric division of a progenitor cell generates two daughters with non-identical cell fates, typically one daughter remains a progenitor while the other commits to a defined cell lineage through differentiation [1]. During development and in adult stem cells, ACDs allow for the maintenance of the stem/progenitor cell pool as well as the generation of differentiated cells. While adult stem cells can also undergo symmetric divisions with subsequent differentiation, there is now compelling data that a number of tissue-specific stem/progenitor cells, including those of the neuronal, hematopoietic, muscle and epidermal lineages, undergo ACD [2-6]. This work was made possible and heavily influenced by pioneering studies on ACD in D. melanogaster and C. elegans, which has been reviewed in detail elsewhere [7,8]. Recent work has highlighted the advantages of studying ACD in the epidermis, with novel advances in understanding the many levels at which this process is regulated [5,9,10]. One crucial determinant of ACD is the axis of spindle orientation and it regulation, which is the major focus of this review.The epidermis is a multi-layered epithelium. Development of the epidermis from a single layer of epithelial progenitors is termed stratification (Figure 1A). The innermost cell layer, called the basal layer, lies on top of a basement membrane separating it from the underlying dermis. Cells of this layer undergo symmetric divisions to increase surface area through much of development. Starting around embryonic day 13.5 in the mouse, division orientation changes and the majority of divisions occur with the mitotic spindle oriented along the apical-basal axis of the cell [5,11]. These divisions are referred to as asymmetric. Definitive evidence for cell fate asymmetry of these divisions was recently reported [9]. Short-term line