Patterning is a fundamental process that allows tissues to develop complexity through the use of relatively simple Yules'. Through our studies of patterning and cell death in the developing Drosophila retina, we have focused on the roles of the transmembrane protein Roughest in regulating cell death and setting pattern. Recent work has demonstrated that Roughest is part of a larger family of proteins that include Neph and Nephrin in vertebrates and Syg-1 and Syg-2 in C. elegans. In vertebrates, these proteins likely regulate a large number of processes. In particular, mutations that abrogate Nephl or Nephrin lead to improper development of the kidney and its slit diaphragm, leading to proteinuria syndromes in mouse and humans. The broad expression patterns of these proteins suggest that other tissues are likely to be affected as well. Mutations in the Nephl ortholog Roughest lead to a block in normal patterning of the 'interommatidial precursor cells' (IPCs). During a discreet stage of eye development, IPCs undergo dramatic cell movements that establish a precise hexagonal lattice of optically insulating support cells. Our data indicate Roughest regulates this process through its adhesion to the Nephrin ortholog Hibris; their mutual, heterophilic adhesion draws the IPCs away from each other to re-organize around the ommatidia array. This process has led us to propose a model in which developing epithelia use heterophilic adhesion to re-organize cells into complex patterns. This Proposal focuses on understanding this process further, by exploring the roles of the Notch and Dpp signaling pathways as well as putative downstream targets identified through our genetic screens and by analogy with work done on Nephl and Nephrin. Our larger goal is to bring a more sophisticated understanding of how adhesion, cell signaling, and cell morphogenesis can act together to create complex cell patterns within developing epithelia. Disease: A broad array of diseases result from defects in intact epithelia including cancer, blindness, and birth defects. Of particular relevance is nephropathy, both inherited and as a result of insults such as metabolic syndrome/diabetes; recent evidence has linked metabolism-mediated defects to alterations in Nephrin and podocyte effacement. Our work seeks to understand the mechanisms that ensures these tissues are built (or rebuilt) properly. The advantage of our model is its emphasis on in situ experimentation.
| Rudrapatna, V A; Bangi, E; Cagan, R L (2014) A Jnk-Rho-Actin remodeling positive feedback network directs Src-driven invasion. Oncogene 33:2801-6 |
| Rudrapatna, Vivek A; Bangi, Erdem; Cagan, Ross L (2013) Caspase signalling in the absence of apoptosis drives Jnk-dependent invasion. EMBO Rep 14:172-7 |
| Johnson, Ruth I; Bao, Sujin; Cagan, Ross L (2012) Interactions between Drosophila IgCAM adhesion receptors and cindr, the Cd2ap/Cin85 ortholog. Dev Dyn 241:1933-43 |
| Cagan, Ross L (2011) The Drosophila nephrocyte. Curr Opin Nephrol Hypertens 20:409-15 |
| Larson, David E; Johnson, Ruth I; Swat, Maciej et al. (2010) Computer simulation of cellular patterning within the Drosophila pupal eye. PLoS Comput Biol 6:e1000841 |
| Bao, Sujin; Fischbach, Karl-Friedrich; Corbin, Victoria et al. (2010) Preferential adhesion maintains separation of ommatidia in the Drosophila eye. Dev Biol 344:948-56 |
| Cordero, Julia B; Cagan, Ross L (2010) Canonical wingless signaling regulates cone cell specification in the Drosophila retina. Dev Dyn 239:875-84 |
| Cagan, Ross (2009) Principles of Drosophila eye differentiation. Curr Top Dev Biol 89:115-35 |
| Larson, David E; Liberman, Zoe; Cagan, Ross L (2008) Cellular behavior in the developing Drosophila pupal retina. Mech Dev 125:223-32 |
| Seppa, Midori J; Johnson, Ruth I; Bao, Sujin et al. (2008) Polychaetoid controls patterning by modulating adhesion in the Drosophila pupal retina. Dev Biol 318:1-16 |
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