Our lab seeks to understand on how cellular signaling networks establish spatial organization within and among cells, and how this organization drives cell fate decisions in development. In particular, what are the key features of signaling networks that enable the complex long range spatial patterns that we observe in living systems?
Our work currently focuses on cell polarity, which encompasses a number of pathways important for allowing cells to differentiate top from bottom, front from back. This relatively simple concept lies at the heart of many diverse and essential developmental processes in biology, from bacteria to humans. Yet the signaling networks involved are remarkably complex.
A simplified reaction-diffusion model for PAR polarization based on mutual antagonism. See [2] for more details.
The one cell C. elegans embryo is dramatic example of cell polarity, in this case driven by the highly conserved PAR polarity network. Throughout the animal kingdom, PAR proteins regulate many essential processes, including asymmetric and cell fate inheritance during cell division, the establishment of body plans, axon-dendrite specification, cell migration, and the establishment of epithelial tissue architecture. Moreover, defects in the PAR network are associated with numerous developmental defects and cancer.
Our goal is to identify the physical principles that underly pattern generation by the PAR network and how these principles allow for a system that drives polarity in a wide range of cells differing in size, shape, and function. As a model system, we work on early embryonic development of the nematode worm Caenorhabditis elegans. Here, PAR polarity plays a central role in orchestrating in a series of asymmetric cell divisions that are critical for generating the major cell lineages of the adult animal.
PAR polarity first appears in the one-cell embryo, as two groups of antagonistic PAR proteins are segregated into complementary domains along the long axis of the embryo. Polarization of PAR proteins is triggered in response to a large scale reorganization of a highly contractile, membrane-associated actomyosin meshwork, which drives asymmetric transport of PAR proteins within the cell.
Once formed, these so-called PAR domains define the anterior-posterior (A-P) axis of the animal and provide for the spatial regulation of numerous downstream pathways that drive division asymmetry, from the biased microtubule pulling forces that displace the mitotic spindle from the cell center to the unequal partitioning of cytoplasmic cell fate determinants into the daughter cells. This general pattern is then repeated in a series of polarized cell divisions that ultimately restrict germ cell fate into two stem-cell like precursors.
PAR polarity governs asymmetric divisions of the P lineage to restrict germ line cell fate to the two germ-line precursor cells Z2/Z3 (movie).
Genetic approaches have revealed most of the key players and many key interactions. However, bridging the nanometer scale of protein interactions to the formation of cell scale patterns remains elusive. How do dynamic protein interactions yield a stable boundary between PAR domains? What governs the size and position of domains? How is domain size measured and controlled? How is pattern formation coupled to changes in the underlying cytoskeletal meshwork?
To answer these questions, we are taking an integrative approach, combining genetics, pharmacologic, and quantitative imaging-based approaches, along with the formulation and testing of quantitative models for polarity establishment. We have begun to define the mobility of PAR proteins in cells and how these mobilities are controlled to allow enrichment of PAR proteins within domains [1], and to test theoretical models for actin-dependent polarization in the one cell embryo [2].
By analyzing polarization from the molecular to systems-level scale, our work seeks to identify the core features that drive and regulate pattern formation by the PAR protein network, and ultimately determine the consequences of these features for cell polarity in different cells and tissues during development.
[1] Goehring et al. (2011) Journal of Cell Biology. [2] Goehring et al. (2011) Science.