Planar cell polarity (PCP) describes the collective alignment of cells or a group of cells within the plane of a tissue. This phenomenon enables cells to orient themselves within a mass of tissue during various organ formations, including polarization of cardiomyocytes during myocardium development and intraluminal valve in lymphatic vessel. The establishment of PCP involves asymmetrical localization of PCP proteins along the cell membrane, yet the mechanism of how this is achieved and maintained across long range remains poorly defined. The goal of my research is to understand the global cues leading to global alignment of PCP proteins. Directed mechanical forces are one possible polarizing cue that can act over long range to orient cell polarity. Indeed, within tissues that function under constant fluid and contractile stress like the heart and vasculature, mechanical forces can have an instructive role in tissue patterning. What has been lacking is a tractable vertebrate model system that combines the ease of genetic and mechanical manipulation with a simple two-dimensional readout of PCP that can be followed with time-lapse imaging. Using murine epidermis as a model system, I will combine classical genetics and cell biology with biophysical approaches to define the role of directed mechanical forces in coordinating planar polarity.My preliminary data demonstrate that the initiation of PCP coincides both temporally and spatially with anisotropic tissue-scale mechanical tension across the epithelial sheet. Furthermore, disrupting the transmittance of this tension to the epithelium disrupts the global coordination of PCP. Given these findings, I hypothesize that dermal and ECM alignments provide a mechanical cue to basal cells that collectively align planar cell polarity across the epithelial sheet. My working model is that mechanical tension initiates directed trafficking of newly synthesized PCP protein or selective endocytosis of membrane-associated PCP proteins leading to their asymmetric localization along tissue axis. To test this hypothesis, I propose studies with the following aims: 1. To identify the mechanisms driving collective asymmetric distribution of Celsr12. To investigate the sufficiency and/or codependence of individual mechanical forces in generating PCP in vitroTogether, these studies will provide fundamental insights on the establishment of PCP in vertebrate and further our understanding in functional tissue engineering.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2015 → 06/30/2017|