Deciphering the self-assembly rules for multicellular life

The overall aim of the project is to elucidate the molecular processes that govern the transition from single cell to multicellular life. We will investigate polarity development and gastrulation-like events such as symmetry breaking and axial organization, describe dynamics of cell shape in morphospace, and how spatial information is robustly encoded in the structure of cellular aggregates with variable cell fates. Guided by experimental data pertaining to possible reaction pathways, the project hopes to advance our knowledge of the physical processes leading to successful asymmetric cell division, self-assembly of multicellular aggregates, and embryogenesis.Specifically, we will focus on the initial polarity development of a C. elegans zygote - how a fertilised egg cell breaks symmetry and divides asymmetrically into an anterior and a posterior cell. Driving asymmetric cell division is the segregation of the mutually antagonistic anterior and posterior PAR proteins along a polarity axis, through which cortical domains are formed. Through signalling to effector proteins, cortical domain formation then leads to asymmetric redistribution of cell fate determinants, to be unequally inherited by daughter cells. With reference to our model organism C. elegans, this polarity axis is established by sperm entry and centrosome formation, a process which establishes the posterior cell pole. Prior to this the cortex is initially enriched with anterior proteins (aPARs) and devoid of posterior proteins (pPARs), which are instead uniformly distributed in the cytoplasm. In order to polarise, a sufficient perturbation must occur within the system in order to cue symmetry breaking and hence polarisation of the otherwise uniform PAR proteins. Whilst advances in experimental techniques, such genetics, super-resolution imaging by TIRF microscopy, photo-bleaching, and single-particle tracking, have allowed for the identification of key components in the processes governing asymmetric cell division, the physical mechanisms are yet to be described in detail.

Specific aims:

1. Explain polarity development using molecular detailed PAR signalling modules. The model implemented in the work of Nathan Goehring et. al. is a highly simplified version of the highly conserved PAR signalling pathway. As many molecular players have now been discovered, we will investigate their roles by modelling, paying particular attention to issues of energy consumption, redundancy and robustness.

2. Elucidate the role of feedback loops and clustering of PAR-3 and CHIN-1 dependent assemblies in polarity development.
PAR-3 and CHIN-1 are known to oligomerise in order to become sensitive to cortical flow. We will implement mean field and multi-scale particle-based simulations, which can be compared to single-particle tracking experiments in the Goehring lab.

3. Explain arrest and reanimation under anoxia stress.
The reactions rely on phosphorylation by kinase and flow driven by myosin contraction. These active processes depend on energy consumption. Related to recent work in bacteria and yeast, we would like to understand the processes underlying anoxia and develop a biophysical model. Model and simulation results will be compared with data from Joanna Pinto in the Goehring lab, using statistical analysis for comparison such as mean squared displacement analysis from single particle tracking, with a focus on the relationship between dynamic regime and aggregate size.