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Electrical Control of Cell Polarization

Final Report Summary - ECCP (Electrical Control of Cell Polarization)

General objectives of the projects: Cell polarity plays a key role in regulating cell-cell communication, tissue architecture and development. Both internal and external cues participate in directing polarity and feedback onto each other for robust polarization. One poorly appreciated layer of polarity regulation comes from electrochemical signals spatially organized at the level of the cell or the tissue. These signals which include specific ion fluxes, membrane potential gradients, lipid electrostatics or even steady electric fields, emerge from the polarized activation of specific ion transporters, and may guide polarity in wound-healing, development or regeneration. The overall aim of the ECCP project is to understand the molecular basis of the electrochemical regulation of cell polarity.

In the 4 years of this ECCP project, we have advanced considerably on our broad understanding on how external Electric Fields, of physiological magnitude, may influence cell polarity and growth. These studies also served to propose important contribution of natural electrochemical gradients in cells which may contribute to polarized behavior.

One first key contribution used the genetic model system budding yeast, which polarizes for positioning sites of daughter bud emergence, or during mating to grow mating tip projections towards mating partner. We found that small electric fields may orient both budding and mating, but interestingly to different directions. Budding usually occurred towards the cathode (negative electrode) of the EF, while mating tip grew preferentially towards the anode of the EF. Combining the use of candidate screens on yeast mutants, live imaging and optogenetics methods, we proposed a model, in which the EF may alter the membrane potential of cells, and bias downstream polarity (Rho-GTPase, actin..) to the EF direction. Importantly this effect appeared to be mediated by a K+ transporter, Trk1p which contribute to set membrane potential in normal cells. In addition, we suggested that internal membrane charges mediated by the charged lipid phosphatidylserine, were also important for this response. This work was published in 2014 (Haupt et al , Plos Biology 2014) and was accompanied by several reviews from our group (Campetelli, Bonazzi and Minc Cytoskeleton, 2012; Bonazzi and Minc , Wound Care, 2014; Chang and Minc Ann Rev Cell Dev Biol, 2014).

In a second more recent work, we studied in more details the impact of internal membrane charges, generated by charged lipids, such as Phosphatidylserine on cell polarity in fission yeast. We established how distribution of internal charges are controlled at a cellular level, and more importantly how those charges influence the stability and localization of charged GTPases, such as Cdc42 and Rho1 which are instrumental for cell polarity and shape (Haupt and Minc MbOC 2017).

In addition to these projects, we have worked on generic principles regulating cell polarity, by studying the influence of cell mechanics, growth and shapes on internal polarity. All those work performed in yeast led to general knowledge on how polarity may intersect with other physiological factors inside cells. Those lines of research led to the publication of several papers (Bonazzi et al. Dev Cell 2014, Bonazzi et al, Curr Biol, 2015, Davi and Minc, Curr Op in Microbiology, 2015). We expect these data and results to impact the scientific community and the overall knowledge available to our society.