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Suzanne Eaton
Cellular mechanisms of epithelial patterning and morphogenesis
Control of epithelial packing geometry and planar polarity
Previous and current research
One focus of the lab is to understand the mechanisms by which epithelial tissues develop specific junctional packing geometries and coordinate the polarity of external structures in the plane. We began to understand that these two processes are linked when we looked carefully at the phenotypes caused by the planar cell polarity (PCP) mutants. PCP proteins are junctional molecules that polarize their distribution with respect to the proximal distal axis of each cell, forming tightly coupled proximal and distal cortical domains – a process that starts at about 10 hours before hair formation. The polarity of the PCP domains determines the planar orientation of the emerging wing hairs. These proteins are required, not only to polarize the orientation of wing hairs, but also to reorganize irregularly packed larval epithelium into an orderly hexagonal one (Classen et al., 2005). They do this at exactly the same time that they develop coordinated polarity within the plane of the epithelium, so we think the two processes are mechanistically related. Using both genetic and cell biological approaches, we have learned that junction remodelling requires an increase in the dynamic endocytosis and recycling of E-Cadherin, and that the PCP proteins influence Cadherin trafficking – possibly by recruiting molecules required for its delivery to the plasma membrane (Classen et al., 2005). The challenge now is to understand the cell biological and physical principles that guide hexagonal repacking, and how they relate to polarization and activity of the PCP proteins.
Future prospects and goals
While we continue to investigate how PCP proteins regulate membrane trafficking, we have also begun to develop other tools and approaches. First, we are developing new techniques for long-term time-lapse imaging and automated image analysis that allow us to quantitatively describe the dynamic behaviour of junctions and PCP proteins in wild type and mutant cells. Second, using laser ablation we are studying the balance of forces acting at the junctional region and how it changes during the repacking process and in different mutant backgrounds. Finally, in a collaboration with Frank Jülicher’s group at the Max Planck Institute for the Physics of Complex Systems, we are using these data to develop physical models that will help us understand how local cellular adhesive, elastic and contractile properties are influenced by PCP proteins and other molecules, and how they combine to produce specific packing geometries at a global level.
Lipoproteins in Morphogen signaling
Previous and current research
The second focus in the lab is on the role of lipoprotein particles in the trafficking and signalling of morphogens. In 2001, we suggested that lipid-linked morphogens spread on particles we called “argosomes” (Greco et al., 2001). In 2005, we showed that these particles corresponded to lipoproteins: Wingless and Hh associate specifically with the Drosophila lipoprotein Lipophorin (a particle similar to vertebrate ApoB-based lipoproteins). In addition to the biochemical association, we found that these morphogens co-localized extensively with Lipophorin in endosomes of developing wing epithelial cells. The association is functionally important, because RNAi-mediated knock-down of Lipophorin reduces long-range Wg and Hh signalling (Panakova et al, 2005). Ongoing work in the lab is directed at understanding how lipoproteins function in morphogen signalling.
One possible advantage of signalling in the context of a particle, rather than as a free protein, is the potential for additional regulation by other particle-associated proteins. In support of this idea, we have recently found that Hh signalling can be potentiated by binding of the glypican Dally to the same particles (Eugster et al, 2007).
Future prospects and goals
Another interesting possibility is that lipoproteins may influence signalling by delivering specific bioactive lipids. Using mass spectrometry, we are defining the Lipophorin lipidome to identify molecules of potential interest. In a complementary approach, we are exploiting the sterol auxotrophy of Drosophila to identify sterol derivatives with important signalling functions. Finally, understanding these events will require a comprehensive understanding of the molecules and mechanisms that control lipoprotein trafficking in the developing wing. To this end, we are examining the influence classical lipoprotein receptors, heparan sulfate proteoglycans, as well as lipid-linked morphogens and their receptors on the uptake and subsequent trafficking of these important particles.
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Selected publications
Eugster, C., Pankova, D., Mahmoud, A. and Eaton, S. (2007): Lipoprotein-Heparan sulfate interactions in the Hedgehog pathway. Dev. Cell in press.Marois, E., Mahmoud, A. and Eaton, S. (2006): The endocytic pathway and formation of the Wingless morphogen gradient. Development 133:307-17.
Classen, A, Anderson, K., Marois, E. and S. Eaton. (2005): Hexagonal packing of the Drosophila wing epithelium by the Planar Cell Polarity Pathway. Dev. Cell 9:1-13
Panakova, D., Sprong, H, Marois, E. Thiele, C. and S. Eaton (2005): Lipoprotein particles carry lipid-linked proteins and are required for long-range Hedgehog and Wingless signalling. Nature 435: 58-65.
Greco, V. , Hannus, M., and S. Eaton. (2001): Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106: 633-45.