Nathan Goehring: Projects

Current work in the Developmental Systems lab focuses on the conserved PAR polarity network using the nematode worm Caenorhabditis elegans as a model system. Although the PAR network plays essential roles in all animals, including humans, embryos of C. elegans are a particularly good system for investigation. Embryonic development, including the establishment of polarity, is reproducible and rapid. Early developmental stages are accessible to both physical and chemical manipulation as well as live imaging. Moreover, there is a robust set of genetic and RNAi-based tools that allow us to probe PAR protein function in live developing animals.

Figure 1

Figure 1. C. elegans embryo polarization.

Time-lapse images of an embryo undergoing polarisation. Embryos are initially unpolarised with aPARs localised throughout the membrane (e.g. PAR-6, red). Polarisation is induced through a dramatic rearrangement of non-muscle myosin 2 (NMY-2, white), which coincides with the appearance of a posterior domain (PAR-2, cyan). Cortical myosin is then down-regulated, leaving two PAR membrane domains.

The first cell division of C. elegans embryos is highly asymmetric, giving rise to a large anterior somatic cell and a small, posterior, stem-cell like germ cell. The PAR network is essential for both the size and fate asymmetry of this division. For asymmetric cell division to occur, PAR proteins must first segregate within the cell membrane to generate anterior and posterior domains (Figure 1). These domains then signal to the cell interior to trigger both the asymmetric placement of the division site and the partitioning of germ cell determinants into the posterior half of the embryo so that they are unequally inherited at cytokinesis to generate daughter cells with different fates. The goal of our current research is to reveal the physical mechanisms that drive this segregation of PAR proteins within cells.

Exploring the dynamic nature of PAR proteins

We recently showed that PAR proteins are highly dynamic, reversibly switching between a rapidly diffusing cytoplasmic state, and a more slowly diffusing membrane-associated state (Goehring et al. JCB 2011). This dynamic behaviour has important implications for how these molecules can be segregated into opposing halves of the cell membrane. What features of these proteins are responsible for such dynamic properties? How do proteins associate with the membrane? How is this association regulated in time and space? We aim to tackle these questions using a combination of biophysical measurement, genetic and chemical manipulations, and biochemistry.

Mechanochemical coupling between the cytoskeleton and PAR proteins

A key event in the establishment of PAR polarity in the embryo is the initial induction of asymmetry in the so-called anterior PAR proteins. These proteins are initially segregated into the anterior in association with a dramatic rearrangement of the actomyosin cortex, a thin, highly contractile cytoskeletal layer just under the membrane. At the onset of polarity, the cortex, which initially forms a highly contractile network throughout the entire embryo, retracts and flows towards the anterior (Figure 1). This flow appears to transport anterior PAR proteins along with it, suggesting that the biochemical PAR network is somehow coupled to the mechanical cytoskeletal network. On the basics of biophysical measurements of PAR proteins and actomyosin motion, we recently provided evidence that this coupling occurs through a process known as advection (Goehring et al. Science 2011). Importantly, advection does not require direct biochemical interactions between actin and the PAR proteins. Rather, contraction of the actomyosin network results in anterior-directed flows of cortical cytoplasm. PAR proteins that are embedded within this flowing cortical cytoplasm are transported passively much like objects in a river (Figure 2). What properties of PAR proteins allow them to tap into this transport machinery? Conversely, can PAR proteins modulate cortical flows to drive their own transport? A key focus of the lab will be this interplay between these mechanical (cortex) and biochemical (PAR) systems.

Figure 2

Figure 2. A model for advective polarization of a self-organizing PAR chemical network. This model integrates measured kinetic parameters for anterior and posterior PAR proteins including membrane binding and unbinding rates and diffusion coefficients.  Further, PARs can exchange between the membrane and a cytoplasmic pool and can displace one another from the membrane.  Given appropriate parameter choice this reaction-diffusion system is multi-stable, capable of supporting either an unpolarized or polarized state.  Which state the system will be in, depends on the initial state and what kinds of perturbations are applied.  Our work suggests that advection of PAR proteins by cortical cytoplasmic flow can induce asymmetry in the unpolarized state and thereby triggers the system to switch into the polarized state. (Click to view larger image)

Self-organisation of PAR proteins on cellular membranes

Despite a critical role for the actin cytoskeleton in inducing an initial asymmetry in PAR proteins, recent evidence from our and other labs points increasingly towards a role for self-assembly in PAR domain organisation. Specifically, our work indicates that there are no physical barriers or transport processes required for keeping PAR proteins on the two halves of the cell separate (Goehring, et al. JCB 2011). Rather, once an asymmetry is induced, interactions between PAR proteins appear to be sufficient to promote and maintain the polarised state. These observations point towards a class of reaction-diffusion mechanisms in generating the observed localisation patterns, and indeed, we can recapitulate the observed patterns with a simplified theoretical model (Goehring, et al. Science 2011). Extensive literature on theoretical systems has identified a number of core ingredients required for pattern formation. By combining mathematical modeling with experimental manipulation of embryos, current work is focused on uncovering which core features of the PAR interaction network are critical for pattern formation in the embryo.

 

Nathan Goehring

Nathan Goehring

nate.goehring@crick.ac.uk
+44 (0)20 379 61867

  • Qualifications and history
  • 2006 PhD in Microbiology and Molecular Genetics, Harvard Medical School, USA
  • 2006 Postdoctoral Fellow Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany
  • 2013 Established lab at the London Research Institute, Cancer Research UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK