The long-term objectives of this proposal are to understand the mechanisms that regulate cell polarity during epidermal growth and regeneration. Cell polarity refers to the unequal distribution of cell-cell junctions, cytoskeletal structures and organelles within the cell, and is the most fundamental architectural feature of epithelial tissues. When cell polarity is compromised cells become aberrantly shaped, misoriented, and improperly layered, leading to aberrant control of proliferation, differentiation and tumorigenesis. In highly regenerative adult epithelial tissues such as the skin, dysregulation of stem cells is thought to be an underlying cause of epithelial cancers, so it is critical that cell polarity and tissue architecture is maintained as skin cells continually divide, differentiate and die. While the molecules and mechanisms controlling the establishment of cell polarity are fairly well understood, little is known about how polarity is regulated during tissue regeneration. Because the mammalian skin is one of the most strikingly polarized and regenerative tissues in nature, it is an ideal system to study the regulation of polarity during regeneration. My preliminary data identify a novel mechanism controlling the spatial distribution of polarity proteins in epidermal stem cells undergoing mitosis. I hypothesize that epithelial polarity is maintained during growth and regeneration through cell cycle-dependent regulation of polarity protein localization. To test this central hypothesis I will: 1) characterize the spatial and temporal dynamics of polarity protein localization during mitosis;2) define the mechanisms controlling polarity protein dynamics during mitosis;and 3) determine how regulation of polarity in mitotic epidermal cells contributes to the maintenance of global tissue architecture. The dynamics and mechanisms of polarity protein localization during mitosis will be identified during the mentored phase, and follow up on newly identified mechanisms and protein interactions will be accomplished during the independent phase. Decifering the mechanisms that regulate polarity in proliferative epidermal stem cells will be fundamentally important to the long-term objective of understanding how defects in polarity maintenance can lead to human disease.
|Devenport, Danelle; Oristian, Daniel; Heller, Evan et al. (2011) Mitotic internalization of planar cell polarity proteins preserves tissue polarity. Nat Cell Biol 13:893-902|