Establishment of Long-Range Tissue Polarity in a Regenerative Epithelium
How cells assemble into complex arrangements that enable the specialized function of a tissue is one of the most fundamental questions in biology. During development, cells acquire information about their position, identity, and orientation, which together enable the formation of specialized organs. How directional signals orient cells within a tissue is perhaps the least understood of these developmental processes. My lab’s primary focus is to understand how cells send, receive, and interpret directional cues via the planar cell polarity pathway and in response assemble coordinately polarized cellular structures across tissues.
The planar polarity pathway (PCP) can be thought of as the cells’ compass, instructing cells about which direction to move, divide, or assemble subcellular structures. These planar polarized events align in a coordinated fashion across entire tissues, indicating that directional signals are communicated over extremely long distances. Defects in PCP essentially cause cells to lose their sense of direction and result in severe developmental disorders such as neural tube defects, cystic kidney disease, hearing loss, ciliopathies, and heart abnormalities.
My lab uses the mammalian epidermis, one of the most strikingly polarized tissues in nature, as a model system to elucidate conserved mechanisms of PCP. Amenable to genetics, the mouse epidermis is also the largest and most accessible organ in the body allowing for biochemical, proteomic, and genome-wide transcriptional analyses that have not been possible in predominant invertebrate model systems where tissue abundance has been limiting. Furthermore, the use of organotypic and primary cell cultures ex vivo enables live imaging, biophysical approaches, and rapid mechanistic analyses that are limited in other mouse genetic systems. We use a powerful combination of genetic, genomic, proteomic, imaging, and biophysical approaches to understand how directional cues organize planar tissue polarity and elucidate how, in response to these cues, cells orchestrate polarized cellular behaviors.
The fundamental mechanisms revealed are likely to be conserved across vertebrate tissues and will ultimately help our understanding of how PCP misregulation can lead to devastating developmental defects. Furthermore, understanding how directional signals orchestrate three-dimensional tissue organization will greatly advance therapeutic approaches aimed at engineering functional organs in vitro.