Proliferating eukaryotic cells actively maintain size homeostasis by coupling cell size to cell division. To do so cells must integrate analog information (i.e. cell size or a proxy for size) and convert it into a digital all-ornone decision to divide. While recent work has provided key insights into size homeostasis strategies in bacteria and yeasts, eukaryotic size control remains poorly understood in animals and other taxa. The project investigates size control in a uniquely advantageous model, the unicellular alga Chlamydomonas reinhardtii (Chlamydomonas), where prolonged growth in the G1 period allows individual cells to grow in size up to thirty-fold. At the end of G1, mother cells undergo a rapid series of alternating genome replications and divisions to produce 2n uniform-sized daughters, where n is the number of division cycles. This cell cycle has features in common with some animal early embryonic cell cycles and is controlled by regulators that have homologs or close analogs in animals. How commitment to division occurs, and how Chlamydomonas cells count the correct number of subsequent rapid division cycles to achieve cell size homeostasis has remained a mystery. Deterministic models, when applied to Chlamydomonas, are unable to recapitulate observed cell division behavior because they fail to capture stochastic effects. Our prior studies have found Stochastic Hybrid Systems (SHS) that integrate continuous dynamics with random discrete events, to be a powerful framework for modeling size of individual cells across multiple generations. Preliminary analysis of these systems have led to new mathematical results on the forms of coupling between cell size and timing of division essential for maintaining size homeostasis. Combining SHS based models with single-cell measurements of size and gene expression in wild type and cell-cycle mutants, this study will characterize biomolecular circuits mediating size control in Chlamydomonas.

Public Health Relevance

Diseases of cell proliferation such as cancer frequently involve deregulation of control mechanisms that couple cell growth, cell size and cell division. This project uses novel modelling approaches for uncovering size control principles in a uniquely tractable experimental organism, Chlamydomonas. The principles that emerge from this modelling study are expected to be applicable to more complicated cell types, including human cells, where complex stochastic behaviors related to cell division are poorly understood.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM126557-02
Application #
9538792
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Resat, Haluk
Project Start
2017-08-03
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Delaware
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
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Vargas-Garcia, Cesar A; Ghusinga, Khem Raj; Singh, Abhyudai (2018) Cell size control and gene expression homeostasis in single-cells. Curr Opin Syst Biol 8:109-116
Mena, Adriana; Medina, Daniel A; García-Martínez, José et al. (2017) Asymmetric cell division requires specific mechanisms for adjusting global transcription. Nucleic Acids Res 45:12401-12412