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Mechanisms of cell polarization in response to external cues

English title Mechanisms of cell polarization in response to external cues
Applicant Martin Sophie
Number 155944
Funding scheme Project funding
Research institution Département de Microbiologie Fondamentale Faculté de Biologie et de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Cellular Biology, Cytology
Start/End 01.01.2015 - 31.03.2018
Approved amount 859'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Experimental Microbiology

Keywords (6)

Ras; Cdc42; Cell fusion; Fission yeast schizosaccharomyces pombe; Cell polarization; Pheromone

Lay Summary (French)

Lead
Les cellules, qui forment l'unité fondamentale de la vie, sont spatialement organisées en zones d'activités diverses. Cette organisation spatiale, ou polarisation, est nécessaire à leurs fonctions, par exemple pour contrôler la croissance ou la division cellulaire, ou encore la migration des cellules lors de réparation tissulaire. Conceptuellement, trois étapes menant à la polarisation cellulaire peuvent être distinguées: premièrement la cellule perçoit un signal qui conduit à marquer une région corticale de la cellule. Ensuite, une machinerie moléculaire est recrutée au site marqué. Finalement, cette machinerie recrute des effecteurs qui réorganisent la cellule et forment l'axe de polarisation. Ces concepts, et la nature moléculaire de ces étapes, ont été largement conservés au cours de l'évolution et peuvent donc être étudiés dans des systèmes modèles simples, tels que la levure.
Lay summary

Dans ce projet, nous étudions les mécanismes moléculaires qui servent aux cellules de levure à trouver, puis fusionner avec une cellule partenaire pour former un zygote, lors de la reproduction sexuelle. Pendant la différenciation sexuelle, les cellules expriment des phéromones qui sont reconnues par de potentielles cellules partenaires. La perception de la source de phéromone permet la croissance des cellules l'une vers l'autre, suivi de leur fusion (de même qu'un spermatozoïde se dirige puis fusionne avec l'ovule).

Nous avons récemment décrit comment la machinerie moléculaire de polarisation, dont l'acteur principal, Cdc42, est une petite protéine de la famille des GTPases, initialement explore la périphérie des cellules de levures pendant leur différenciation sexuelle, puis est stabilisée et permet la croissance polarisée des cellules l'une vers l'autre et finalement leur fusion. Nous cherchons à comprendre les liens moléculaires entre la perception de la phéromone par son récepteur et Cdc42, et comment sont contrôlées les transitions entre exploration, stabilisation et fusion. Une partie du projet se penche sur un candidat potentiel, une autre petite protéine de la famille des GTPases, Ras1. Une deuxième partie du projet cherche à décrire les étapes moléculaires de la fusion entre les deux cellules partenaires, en utilisant des approches de génétique, génomique, microscopie à fluorescence et microscopie électronique.

Ceci est un projet de recherche fondamentale, qui nous permettra de mieux appréhender les mécanismes de polarisation et de fusion cellulaire. Les acteurs moléculaires étudiés sont important à la fonction cellulaire de façon générale (Ras est un important oncogène chez l'homme par exemple). Leur étude dans un organisme modèle permettra de mieux comprendre leur fonction.

 

Direct link to Lay Summary Last update: 25.09.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Gamete fusion triggers bipartite transcription factor assembly to block re-fertilization
Vještica Aleksandar, Merlini Laura, Nkosi Pedro Junior, Martin Sophie G. (2018), Gamete fusion triggers bipartite transcription factor assembly to block re-fertilization, in Nature, 560(7718), 397-400.
Exploration and stabilization of Ras1 mating zone: A mechanism with positive and negative feedbacks
Khalili Bita, Merlini Laura, Vincenzetti Vincent, Martin Sophie G., Vavylonis Dimitrios (2018), Exploration and stabilization of Ras1 mating zone: A mechanism with positive and negative feedbacks, in PLOS Computational Biology, 14(7), e1006317-e1006317.
Inhibition of Ras activity coordinates cell fusion with cell-cell contact during yeast mating
Merlini Laura, Khalili Bita, Dudin Omaya, Michon Laetitia, Vincenzetti Vincent, Martin Sophie G (2018), Inhibition of Ras activity coordinates cell fusion with cell-cell contact during yeast mating, in J Cell Biol, 217, 1467.
A systematic screen for morphological abnormalities during fission yeast sexual reproduction identifies a mechanism of actin aster formation for cell fusion
Dudin Omaya, Merlini Laura, Bendezu Felipe, Groux Raphael, Vincenzetti Vincent, Martin Sophie G (2017), A systematic screen for morphological abnormalities during fission yeast sexual reproduction identifies a mechanism of actin aster formation for cell fusion, in PLoS Genet, 13, e1006721.
Live Cell Imaging of the Schizosaccharomyces pombe Sexual Life Cycle
Merlini Laura, Vjestica Aleksandar, Dudin Omaya, Bendezu Felipe, Martin Sophie G (2017), Live Cell Imaging of the Schizosaccharomyces pombe Sexual Life Cycle, in Hagan Iain M, Carr Antony M, Grallert Agnes , Nurse Paul (ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 795.
Local Pheromone Release from Dynamic Polarity Sites Underlies Cell-Cell Pairing during Yeast Mating
Merlini Laura, Khalili Bita, Bendezu Felipe, Hurwitz Daniel, Vavylonis Dimitrios, Martin Sophie G (2017), Local Pheromone Release from Dynamic Polarity Sites Underlies Cell-Cell Pairing during Yeast Mating, in Current Biology, 26, 1117.
Microscopy of Fission Yeast Sexual Lifecycle
Vjestica Aleksandar, Merlini Laura, Dudin Omaya, Bendezu Felipe, Martin Sophie G (2016), Microscopy of Fission Yeast Sexual Lifecycle, in J Vis Exp, 109, -.
Role and organization of the actin cytoskeleton during cell-cell fusion
Martin Sophie G (2016), Role and organization of the actin cytoskeleton during cell-cell fusion, in Semin Cell Dev Biol, 60, 121.
Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion
Dudin Omaya, Merlini Laura, Martin Sophie G (2016), Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion, in Genes and Development, 30, 2226.
Spontaneous cell polarization: Feedback control of Cdc42 GTPase breaks cellular symmetry
Martin Sophie G (2015), Spontaneous cell polarization: Feedback control of Cdc42 GTPase breaks cellular symmetry, in Bioessays, 1193.

Collaboration

Group / person Country
Types of collaboration
Bruno Humbel / Electron Microscopy Facility of the University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
138177 Cell polarization in response to intra- and extracellular cues in fission yeast 01.01.2012 Project funding
176396 Mechanisms of cell polarization initiation 01.04.2018 Project funding
177127 Real-time super resolution microscopy for microbial cell biology in 4D 01.05.2018 R'EQUIP

Abstract

Cells are highly spatially organized, through mechanisms that are conceptually and molecularly very conserved. One can define three steps for cell polarization. First, landmarks positioned in response to intrinsic or extracellular signals mark a cortical site. Second, small G proteins of the Rho/Ras family, such as Cdc42, become locally activated. Third, these recruit effectors and activate signaling pathways to transduce this spatial information into productive cell organization. In this series of events, the Cdc42 module is constantly re-used, not only in response to distinct landmarks, but also to produce distinct polarization outcomes. How are distinct polarity states achieved and regulated? The unicellular yeast models have been instrumental in deciphering the mechanisms of cell polarization and establishing these basic concepts. We have recently described that mating fission yeast cells sequentially exhibit distinct polarization states: at low pheromone levels, cells first display an exploratory state, where the polarization machinery appears active, but fails to recruits cell wall enzymes for polarized growth; at higher pheromone levels, cells then show a polarized growth state as they extend a projection towards a mate; finally, the effective polarization shifts to the organization of a cell-cell fusion machinery for zygote formation. This proposal asks how transition through these states is controlled and how the cell-cell fusion machinery is eventually assembled. There are two specific aims: Aim 1: Role of Ras GTPase in regulating pheromone-dependent polarization statesHow pheromone perception is transduced into spatial cellular organization is unclear, but the sole fission yeast Ras GTPase likely play a central role, as it is required for both signal transduction and cell polarization. Further, deletion of the Ras1 negative regulator, its GTPase Activating Protein Gap1, enhances the cell polarization response in low levels of pheromone, suggesting that Ras1 activity levels modulate the polarization response. We will define the molecular mechanisms by which Ras1 becomes activated at sites of pheromone perception, as well as the mechanisms by which pheromone signaling modulates Ras1 activity. We will also strive to separate the functions of Ras1 in signaling from its spatial role in cell polarization, and investigate where it acts. Our work will define the mechanisms by which a graded external signal is converted to a binary spatial cell response. This is a general cellular problem and the molecular players involved are highly conserved (GPCR signaling machinery, RAS and its regulators). The concepts we will uncover are thus likely to be valid beyond the yeast model. Aim 2: Hierarchical description of the cell-cell fusion machineryCell-cell fusion mechanisms are poorly understood in most organisms. We have conducted a systematic screen for mutants defective in the mating process, which identified many fusion mutants, and described several steps in the fusion process. Our aim is to establish a hierarchical description of the parts list for cell-cell fusion, and set up correlative EM-fluorescence microscopy to describe the fusion process. By initiating a systematic study of cell-cell fusion in fission yeast, using the vast array of genetic and cell biological tools available, we aim to provide a model in which a global systems-level understanding can eventually be achieved.
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