Most of our work is focused on the molecular and cellular mechanisms that determine the patterns of synaptic connectivity in the brain. The fruit fly Drosophila is our primary experimental system. Drosophila has unique advantages for the study of brain development, because many of its neural circuits are 'hard-wired' by genetics. This makes it straightforward to study the contributions made by individual genes to brain wiring patterns. Although the fly brain does not resemble a vertebrate brain, the properties of fly and vertebrate neurons are quite similar, and many of the genes involved in Drosophila nervous system development are conserved in humans and other mammals.
Our major focus is on cell-surface proteins (CSPs) that mediate interactions among neurons, and between neurons and other cell types. Together with Chris Garcia's lab at Stanford, we recently characterized a group of immunoglobulin superfamily (IgSF) CSPs that form a complex interaction network. In this network, a subfamily of 21 2-Ig domain CSPs, the Dprs, selectively bind to another subfamily of 9 3-Ig domain CSPs, called DIPs. Each dpr and DIP gene is expressed by a distinct small subset of neurons in the larval CNS and pupal brain. Genetic analysis shows that mutations affecting Dprs and DIPs alter synaptic connectivity in the larval neuromuscular system and pupal/adult optic lobe. Thus, Dprs and DIPs have characteristics that match those predicted for neuronal surface labels that program the patterns of synaptic connections during development.
We also work on receptor tyrosine phosphatases (RPTPs). These are a family of neuronal cell-surface receptors that are involved in axon guidance and synaptogenesis. We conducted loss-of-function and gain-of-function screens to identify cell-surface ligands that bind to the RPTPs, and are characterizing a number of these. One ligand, Stranded at second (Sas), interacts with the Ptp10D RPTP in cis and in trans. Sas is an important determinant of glial cell fate, and trans interactions between glial Sas and neuronal Ptp10D regulate glial Sas signaling. Sas has the ability to move glial transcription factors from the nucleus to the cell membranes. Sas also regulates glial proliferation, and glial overexpression of Sas in larvae lacking Ptp10D produces invasive glioblastomas. We are currently studying the mechanisms underlying these phenomena.
Finally, we are developing new ways to systematically generate monoclonal antibodies (mAbs) against native CSPs in an assembly-line manner, so that we can rapidly make mAbs against large CSP collections. We are applying these methods to human CSPs involved in cancer and in regulation of the immune system. Such mAbs are likely to be useful for basic research on human cancer and immunology, and may also have therapeutic potential.