Phosphoregulation of the cytokinetic protein Fic1 contributes to fission yeast growth polarity establishment

ABSTRACTCellular polarization underlies many facets of cell behavior, including cell growth. The rod-shaped fission yeast Schizosaccharomyces pombe is a well-established, genetically tractable system for studying growth polarity regulation. S. pombe cells elongate at their two cell tips in a cell cycle-controlled manner, transitioning from monopolar to bipolar growth in interphase when new ends established by the most recent cell division begin to extend. We previously identified cytokinesis as a critical regulator of new end growth and demonstrated that Fic1, a cytokinetic factor, is required for normal polarized growth at new ends. Here, we report that Fic1 is phosphorylated on two C-terminal residues, which are each targeted by multiple protein kinases. Endogenously expressed Fic1 phosphomutants cannot support proper bipolar growth, and the resultant defects facilitate the switch into an invasive pseudohyphal state. Thus, phosphoregulation of Fic1 links the completion of cytokinesis to the re-establishment of polarized growth in the next cell cycle. These findings broaden the scope of signaling events that contribute to regulating S. pombe growth polarity, underscoring that cytokinetic factors constitute relevant targets of kinases affecting new end growth.This article has an associated First Person interview with Anthony M. Rossi, joint first author of the paper.

A hybrid stochastic–deterministic mechanochemical model of cell polarization

At the onset of cell locomotion, cells break symmetry to form well-defined cell fronts and rears through the process of cellular polarization. Using an in silico approach, we have identified one of the simplest quantitative frameworks as a possible mechanochemical mechanism for spontaneous cell polarization.

Resident and elicited macrophages differ in expression of their glycomes and lectins

The pleiotropic functions of macrophages in immune defense, tissue repair, and maintenance of tissue homeostasis are supported by the heterogeneity in macrophage sub-populations that differ both in ontogeny and polarization. Although glycans and lectins are integral to macrophage function, little is known about the factors governing their expression. Here we show that the cellular glycome of murine peritoneal macrophages primarily reflects developmental origin and to a lesser degree, cellular polarization. Resident macrophages were characterized by a simple glycome, predominantly consisting of core 1 O-glycans, while elicited macrophages also expressed core 2 O-glycans, along with highly branched and extended complex-type N-glycans, that exhibited a higher N-acetylneuraminic acid:N-glycolylneuraminic acid ratio. Strikingly, our analysis revealed that resident and elicited macrophages express 139 lectin genes, with differential expression of 49 lectin genes, including galectins, Siglecs, and C-type lectins. These results suggest that regulation of self-glycan-protein complexes may be central to macrophage residence and recruitment.

Reconstruction of Par-dependent polarity in apolar cells reveals a dynamic process of cortical polarization

Cellular polarization is fundamental for various biological processes. The Par network system is conserved for cellular polarization. Its core complex consists of Par3, Par6, and aPKC. However, the general dynamic processes that occur during polarization are not well understood. Here, we reconstructed Par-dependent polarity using non-polarized Drosophila S2 cells expressing all three components endogenously in the cytoplasm. The results indicated that elevated Par3 expression induces cortical localization of the Par-complex at the interphase. Its asymmetric distribution goes through three steps: emergence of cortical dots, development of island-like structures with dynamic amorphous shapes, repeating fusion and fission, and polarized clustering of the islands. Our findings also showed that these islands contain a meshwork of unit-like segments. Furthermore, Par-complex patches resembling Par-islands exist in Drosophila mitotic neuroblasts. Thus, this reconstruction system provides an experimental paradigm to study features of the assembly process and structure of Par-dependent cell-autonomous polarity.

Reconstruction of Par polarity in apolar cells reveals a dynamic process of cortical polarization

Cellular polarization is fundamental for various biological processes. The Par network system is conserved for cellular polarization. Its core complex consists of Par3, Par6, and aPKC. However, the dynamic processes that occur during polarization are not well understood. Here, we artificially reconstructed Par-dependent polarity using non-polarized Drosophila S2 cells expressing all three components endogenously in the cytoplasm. The results indicated that elevated Par3 expression induces cortical localization of the Par-complex at the interphase. Its asymmetric distribution goes through three steps: emergence of cortical dots, development of island-like structures with dynamic amorphous shapes, repeating fusion and fission, and polarized clustering of the islands. Our findings also showed that these islands contain a meshwork of unit-like segments. Par-complex patches resembling Par-islands exist in Drosophila mitotic neuroblasts. Thus, this reconstruction system provides an experimental paradigm to study features of the assembly process and structure of Par-dependent cell-autonomous polarity.

A quantitative network modeling approach to evaluate the role of cytokine combinations on CD4+ T cell differentiation, partial polarization, and plasticity

Diverse cellular polarization states with different phenotypes and functions are derived from the differentiation of activated CD4+ T naïve lymphocytes in the presence of particular cytokines. In addition, conversion of polarized cells to phenotypes different from that originally induced has been documented, highlighting the capacity of the immune response for adaptation to changing circumstances. In a recent study, we proposed a minimal Boolean regulatory network of CD4+ T differentiation that incorporates transcription factors, signaling pathways, and autocrine and exogenous cytokines. The qualitative model effectively reproduced the main polarized phenotypes of CD4+ T cells and several of the plasticity events reported in the literature. Yet, the amount and the expression of cytokines relative to expression of other factors influence CD4+ T cell transitions. In this paper, we have extended the Boolean network to a continuous model that allows us to assess the effect of quantitative differences in the concentrations and combinations of exogenous and endogenous cytokines, as well as diverse levels of transcription factors expression, in order to assess the role of intracellular and extracellular components in CD4+ T differentiation and plasticity. Interestingly, the model predicts either abrupt or gradual differentiation patterns between observed phenotypes depending on critical concentrations of single or multiple environmental cytokines. Plastic changes induced by environmental cytokines were observed in conditions of partial phenotype polarization in the Th1/Th2 transition. On the other hand, the Th17/iTreg transition was highly dependent on cytokine concentrations in the environment. Thus, modeling shows how the concentration of exogenous factors, the degree of initial polarization, and cell heterogeneity, may determine the differentiation and plasticity capacity of CD4+ T cells. The model and results presented here are useful to further understand system-level mechanisms underlying observed patterns of CD4+ T differentiation and plasticity.

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

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.

Modulation of cellular polarization and migration by ephrin/Eph signal-mediated boundary formation

Compartment boundaries are essential for ensuring proper cell organization during embryo development and in adult tissues, yet the mechanisms underlying boundary establishment are not completely understood.

Modelling the emergence of polarity patterns for the intercellular transport of auxin in plants

The hormone auxin is actively transported throughout plants via protein machineries including the dedicated transporter known as PIN. The associated transport is ordered with nearby cells driving auxin flux in similar directions. Here, we provide a model of both the auxin transport and of the dynamics of cellular polarization based on flux sensing. Our main findings are: (i) spontaneous intracellular PIN polarization arises if PIN recycling dynamics are sufficiently nonlinear, (ii) there is no need for an auxin concentration gradient and (iii) ordered multi-cellular patterns of PIN polarization are favoured by molecular noise.