Proper functioning of the nervous system requires a precise pattern of connections among nerve cells. We are interested in understanding the mechanisms that produce this wiring pattern. What tells a nerve which way to grow to find its proper target cells? How does the genome coordinate expression of all the cues that direct the growth decisions of each nerve? Given the complexity of the wiring pattern, why are wiring errors so rare? Some years ago, we found that the cell surface receptor, Notch, is required for growth and guidance of particular axons during development, specifically those axons that grow along cells that express the Notch ligand, Delta. Notch is a ubiquitous gene, found in all multicellular animals, and in each species it controls the development of tissues throughout the organism. In humans, improper function of Notch genes is associated with disease, including vascular and immune defects, neurodegeneration and cancer. It is known that Notch exerts many of its effects by directly altering expression of genes in a cell's nucleus. Our analysis of Notch-dependent axon guidance in Drosophila, however, has now demonstrated that Notch also induces a second cascade of effects on cell behavior that had not previously been recognized. We find that Notch determines the shapes of cells and their ability to adhere to and migrate over their neighbors, by regulating a signaling system defined by the homolog of a mammalian oncogene, the Abl tyrosine kinase. In particular, we found that Notch protein physically associates with the accessory factors that cooperate with Abl kinase, and that altering Notch activity modifies the efficacy of Abl signaling. In flies, disturbing the Notch-Abl interaction leads to improper nervous system wiring. Consistent with this, removing the sites on Notch that allow physical interaction with Abl pathway components cripples the ability of Notch to modulate Abl activity and thus to modulate nerve guidance. Based on the roles of cell morphogenesis, adhesion and migration in Notch-associated disease processes, it seems very likely that the novel Notch signaling pathway we have discovered contributes significantly to the mechanism by which dysregulation of Notch genes produces human disease. In a second line of studies in the lab, we have been trying to understand how the genome can specify the incredible complexity of nervous system connections when the nervous system has so many more cells than the genome has genes. We identified a gene control protein, called Lola, that specifies many aspects of nervous system wiring. We found that Lola is made in 20 different forms, and since these can combine in dimeric combinations, Lola is likely to be present in well over 100 different kinds of protein complexes in vivo. In the past year, we have collaborated with the lab of Liqun Luo, at Stanford, to show that this diversity of forms of Lola protein indeed helps specify a diversity of patterns of neural connections. Lola is required (among other things) to set up connections of Drosophila olfactory sensory neurons to higher """"""""cognitive"""""""" centers. We found that different forms of Lola protein help segregate the signals from different odorant receptor neurons, thus shaping the percepts produced by different odorants. By showing how one gene can produce many distinct protein functions these data help to close the gap between the complexity of the nervous system and the paucity of gene control proteins available to encode that complexity.
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