Quantitative modeling of the PAR polarity network


goehring2

Supervising PI

Nathan Goehring (website)

ESR2 Rukshala Vidumini Illukkumbura

Project Description

Background

PAR proteins were identified in C. elegans over 20 years ago. However, it remains unclear how the mobilities of and interactions between individual PAR components combine to generate patterns at the cellular scale, let alone how they provide a system that is robust and adaptable to divergent cell types. Understanding these emergent behaviors requires mathematical modeling of the PAR network informed by experimentally determined parameters governing protein mobility and interaction affinities. In this project we will take a systems-level approach to defining the mobilities of, and interactions between PAR proteins and use this data to guide implementation of new models for self-organisation of PAR polarity.

Objectives

  • Define dynamic behavior of PAR proteins in vivo / in vitro.
  • Definite potential interactions between PAR proteins in vitro / ex vivo.
  • Generate comprehensive model for PAR self-organisation.

Summary of Results

Our understanding of the function of the PAR network is currently hampered by a general lack of quantitative understanding of how molecules move in cells, how they respond to each other and to signals from the environment, including mechanical cues, to polarize cells.

We have sought to remedy this need through the use quantitative imaging and single particle tracking analysis to inform mathematical models and reveal the design principles of the PAR cell polarity network.

Supported by this funding, our work has provided key insights into how PAR proteins respond to symmetry-breaking cues, how their behaviors give rise to cell scale patterns that define the polarity of cells, and how network behaviors impact stem cell divisions during development.

Key publications

1.        Hubatsch, L., Peglion, F., Reich, J.D., Rodrigues, N.T., Hirani, N., Illukkumbura, R., and Goehring, N.W. (2019). A cell size threshold limits cell polarity and asymmetric division potential. Nat. Phys. In press.

2.        Reich, J.D., Hubatsch, L., Illukkumbura, R., Peglion, F., Bland, T., Hirani, N., and Goehring, N.W. (2019). Regulated Activation of the PAR Polarity Network Ensures a Timely and Specific Response to Spatial Cues. Curr. Biol. 29, 1911-1923.e5. Available at: https://linkinghub.elsevier.com/retrieve/pii/S0960982219304877.

3.        Hirani, N., Illukkumbura, R., Bland, T., Mathonnet, G., Suhner, D., Reymann, A.-C., and Goehring, N.W. (2019). Anterior-enriched filopodia create appearance of asymmetric membrane microdomains in polarizing C. elegans zygotes. J. Cell Sci., jcs.230714.

4.        Illukkumbura, R., and Goehring, N.W. (2019). Working Title: Transport of proteins by flows in polarized cells. Curr. Opin. Cell Biol. (in preparation)