A long standing biological question is how cells sense their size and coordinate it with cell divisionet . We have described a new pathway controlling cell size at division in fission yeast relying on a spatial gradient of Pom1/DYRK kinase that influences the activity of a Wee1 regulatory pathway for mitotic entry controlled by Cdr2/SAD kinase. How Pom1-Cdr2 module functions in molecular terms is not yet understood. Moreover, other cell size sensors may function in parallel.
Our objectives were to determine how cell size is sensed and coupled with cell cycle progression and to study the crosstalk between cell mechanics and cell growth and cell cycle progression.
We used fission yeast as well as mammalian cells and developed new methods aiming at monitoring cell cycle progression in live single cells, measuring cell size, monitoring mechanical properties (thickness and elasticity) of the cell wall during growth and shape changes and controlling the growth of single cells through various chemical and mechanical means. These methods were combined with mathematical modeling of cell growth.
Our studies have first defined new mechanisms operating in the Pom1/Cdr2 system that controls fission yeast cell size i/ to promote Wee1-dependent inhibition of mitotic entry until cells are long enough and ii/ to reset Pom1/Cdr2 system in newly born cells after cell division using the SIN signaling pathway. They have demonstrated the absence of cell size control at the G1/S transition in this system.
Second, our studies have demonstrated complex interplays between growth, mechanics and polarity, which enlighten into the control of single cell elongation and consequent size regulation during the cell cycle.
Third, they have shown that mammalian cells swell during mitosis by decreasing their density which might contribute cell rounding up. They have also demonstrated that the cell volume added across the cell cycle shows little or no correlation to cell birth size, a homeostatic behavior called «adder«.
This project is a fundamental cell biology project coordinated by Anne Paoletti (UMR144 CNRS-Institut Curie) and involving Matthieu Piel (UMR144 CNRS-Institut Curie) and Nicolas Minc (Institut Jacques Monod, UMR7592 CNRS-Université Paris Diderot). It was selected in 2014 and received 412672 € of funding in 4 years for a total cost of the project of 1 812072 €.
Our work has resulted in 9 original articles, 3 reviews and 2 method articles.
Cadart C, Monnier S, Grilli J, Sáez PJ, Srivastava N, Attia R, Terriac E, Baum B, Cosentino-Lagomarsino M, Piel M. 2018. Nat Commun. 9(1):3275.
Haupt A, Ershov D and Minc N, 2018 Current Biology, 28(20):3342-3351.
Davì V, Tanimoto H, Ershov D, Haupt A, De Belly H, Le Borgne R, Couturier E, Boudaoud A and Minc N., (2018) Developmental Cell, 45, 2, p170–182.
Haupt A and Minc N., 2018 J Cell Sci. 131(6). pii: jcs214015. Review article
Haupt A and Minc N, 2017 Mol. Biol. Cell. 28(1):210-220
Rincon SA, Estravis M, Dingli F, Loew D, Tran PT, Paoletti A. 2017 Current Biology 2017; 27:534-542.
Rincon SA, Paoletti A. (2016) 2016. 53:28-38. Review article.
Cadart C, Zlotek-Zlotkiewicz E, Venkova L, Thouvenin O, Racine V, Le Berre M, Monnier S, Piel M. 2017. Methods Cell Biol 139:103-120. Method article
Bonazzi* D, Haupt* A, Tanimoto H, Delacourt D, Salort D, Minc N, 2015 Curr Biol 25(20):2677-83.
Davì V and Minc N, 2015 Curr Opinion Microbiology 28:36-45. Review
Zegman Y, Bonazzi D, Minc N, 2015. Methods Cell Biol; 125:423-36. Method article
Guzmán-Vendrell M, Rincon SA, Dingli F, Loew D, Paoletti A. 2015 J Cell Sci. Aug 1;128(15):2842-53
Zlotek-Zlotkiewicz E, Monnier S, Cappello G, Le Berre M, Piel M. 2015. J Cell Biol. Nov 23;211(4):765-74.
Cadart C, Zlotek-Zlotkiewicz E, Le Berre M, Piel M, Matthews HK. 2014 Apr 28;29(2):159-69.
A long standing biological question is how cells sense their size and coordinate it with cell division to control cell size homeostasis. We have described a new pathway controlling cell size at division in fission yeast relying on a spatial gradient of Pom1/DYRK kinase that influences the activity of a Wee1 regulatory pathway for mitotic entry controlled by Cdr2/SAD1 kinase. This pathway also contributes to geometrical sensing of the cell middle and promotes medial division. How Pom1-Cdr2 module functions in molecular terms is not yet understood molecularly. Moreover, other cell size sensors that may function in parallel to confer robustness to cell size homeostasis need to be identified. We thus propose to use fission yeast excellent genetics and to develop new approaches based on micro-fabrication and innovative imaging technics to describe new cell size sensing mechanisms coordinating cell growth and division from yeast to mammals. We will specifically 1/ determine how the Pom1/Cdr2 system controls mitotic entry and establish whether it acts as an active cell size sensor in G2/M; 2/ study the mechanisms of G1/S control of cell size at division; 3/ study the crosstalks between mechanics and cell cycle; 4/ explore the mechanisms of cell size sensing in mammalian cells. This interdisciplinary project will bring about important conceptual advances on the long lasting question of cell size control for cell division from yeast to mammals. These studies promise to have broad impact in our understanding of basic cellular principles relevant to nearly all cells. Our project may also open new options for medicine, especially in the field of cancer diseases where cell division, growth and volume are subject to strong regulation defects.
Madame Anne PAOLETTI (INSTITUT CURIE - SECTION DE RECHERCHE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IC1 INSTITUT CURIE - SECTION DE RECHERCHE
IC2 INSTITUT CURIE - SECTION DE RECHERCHE
IJM Institut Jacques Monod
Help of the ANR 412,672 euros
Beginning and duration of the scientific project: September 2014 - 36 Months