Many roads to symmetry breaking: molecular mechanisms and theoretical models of yeast cell polarity

Abstract

Mathematical modeling has been instrumental in identifying common principles of cell polarity across diverse systems. These principles include positive feedback loops that are required to destabilize a spatially uniform state of the cell. The conserved small G-protein Cdc42 is a master regulator of eukaryotic cellular polarization. Here we discuss recent developments in studies of Cdc42 polarization in budding and fission yeasts and demonstrate that models describing symmetry-breaking polarization can be classified into six minimal classes based on the structure of positive feedback loops that activate and localize Cdc42. Owing to their generic system-independent nature, these model classes are also likely to be relevant for the G-protein–based symmetry-breaking systems of higher eukaryotes. We review experimental evidence pro et contra different theoretically plausible models and conclude that several parallel and non–mutually exclusive mechanisms are likely involved in cellular polarization of yeasts. This potential redundancy needs to be taken into consideration when interpreting the results of recent cell-rewiring studies.

Once and only once: mechanisms of centriole duplication and their deregulation in disease

“…In one attractive model, STIL is proposed to stabilize PLK4 at the site of procentriole assembly, allowing the remaining PLK4 within the ring to be turned over by self-catalyzed degradation 26,109 . Such a process would be controlled by both PLK4 kinase activity and counteracting phosphatases and would likely involve multiple feed-back loops, as suggested by theoretical modeling of the role of GTPases in symmetry-breaking during yeast cell polarization 114 . If correct, this symmetry-breaking model raises the challenge of understanding how PLK4 is regulated in time and space.…”

A non-linear system patterns Rab5 GTPase on the membrane

“…Similarly, the Cdc42 GEF Cdc24 is coupled 66 to the effector Bem1 (Chenevert et al 1992). Computational modelling revealed a Turing-type 67 mechanism of pattern formation by a minimal system composed of Cdc42, the Bem1/Cdc24 68 complex and GDI (Goryachev and Pokhilko 2008;Goryachev and Leda 2017). In plants, the 69 ROP11 GEF, ROPGEF4, forms a dimer that catalyzes nucleotide exchange but also interacts 70 with the active ROP11 (Nagashima et al 2018).…”

Optogenetics reveals Cdc42 local activation by scaffold-mediated positive feedback and Ras GTPase

“…However, the formation of a Cdc42 activity zone is also thought to rely on positive feedback mechanisms that locally amplify Cdc42 activation. Positive feedbacks are thought to be important for spontaneous symmetry breaking, when cells establish polarity in the absence of internal or external landmarks, for instance during spore germination or upon exposure to homogeneous pheromone signals (Bendezu and Martin, 2013;Bonazzi et al, 2014;Goryachev and Leda, 2017;Johnson et al, 2011;Martin, 2015;Wedlich-Soldner and Li, 2003). Furthermore, the dynamic oscillatory patterns of Cdc42 activity, during vegetative growth (Das et al, 2012;Howell et al, 2012) and sexual reproduction (Bendezu and Martin, 2013;Khalili et al, 2018), are indicative of negative in addition to positive feedback regulations.…”