Spindle Orientation in Skin Development and Homeostasis

Abstract Cell division orientation must be tightly controlled for the generation of normal tissue architecture and cell fates. In the skin, oriented cell divisions promote the stratification of the embryonic epidermis and morphogenesis of hair follicles. In adults, spindle orientation buffers the epidermis against oncogenic insults and tissue overgrowth. Given these important functions, it is paramount to understand the mechanisms by which mitotic spindles are precisely oriented. While some of the proteins required for spindle orientation have been identified, we do not fully understand how this molecular machinery generates forces on astral microtubules to allow accurate control of cell division orientation. Our preliminary studies have identified novel regulators of epidermal spindle orientation. Here we propose studies to undercover the underlying mechanisms by which these proteins affect division orientation. Further, we will use novel mouse models to define how spindle orientation contributes to hair follicle morphogenesis and adult epidermal homeostasis. Together, these data will provide a deeper mechanistic understanding of spindle orientation which has essential functions in epidermal, cardiac and neural development as well as the adaptive immune response. In addition, this work has direct relevance for understanding how spindle orientation controls cell fates in hair development, and how it acts to suppress tissue overgrowth when homeostasis is perturbed.