Throughout biology, from a single-celled bacterium developing into a mother cell and endospore, to the differentiation of gut epithelium in higher eukaryotes and even the morphological changes required in the generation of neurons within the human brain, the ability of a cell to generate intrinsic asymmetry plays a crucial role in development. In higher eukaryotes, this ability to polarize requires the establishment within the cell cortex of domains, which acquire distinct molecular and functional identities. One of the best-studied examples of cortical polarity is the one-celled C.elegans embryo, which undergoes an asymmetric division critical for sequestering the germ cell lineage. Prior to cytokinesis, a complex of conserved polarity proteins (PAR-3, PAR-6 and atypical protein kinase C - aPKC) is segregated to the anterior half of the embryo, while at the same time, a posterior domain containing PAR-1 and PAR-2 forms in the complementary posterior region. While it is believed that mutual antagonism between these anterior and posterior polarity complexes is critical to the formation and maintenance of these domains, the mechanisms underlying this process are poorly resolved and no coherent model has been achieved. This proposal takes a multi-disciplinary approach in order to explore how specific kinetic properties of PAR proteins give rise to discrete and robust cortical domains. To this end I will a) Use confocal microscopy to measure in vivo protein dynamics including cortical diffusion and cortical exchange rates and to quantify boundary gradients; b) Analyze how these parameters are affected by depletion or mutation of specific PAR components, and c) Develop and test quantitative models for maintenance of discrete cortical domains.
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