Molecular Diversity and Function of the Hypervariable Receptor Dscam

My laboratory is interested in understanding molecular mechanisms that control the development of neuronal connectivity. Any assembly of neuronal circuits, simple or complex, is controlled by a series of specific molecular signaling systems that instruct the directional growth of neuronal processes (axons and dendrites). We combine genetic, biochemical and cell biological approaches to study how neuronal surface receptors control these signaling systems during axon guidance and target selection. Our main goal is to understand how neuronal receptors contribute to the exquisite specificity that is required to establish millions of synaptic connections. We identified a Drosophila protein (Dscam) that is a receptor of the immunoglobulin superfamily and highly related to the human protein Down Syndrome Cell Adhesion Molecule (DSCAM). Dscam is functionally required for the proper formation of nerve connections in the CNS and PNS. The Drosophila Dscam gene is highly complex. Through alternative splicing some 38,000-protein isoforms can be formed. All Dscam isoforms share the same overall molecular architecture but differ in four protein domains. Such an extraordinary molecular diversity has previously not been described for any other receptor expressed in the nervous system but is reminiscent of immunoglobulin receptors in the immune system. We propose that different nerve cells express different Dscam isoforms and that this specifies a molecular recognition code that provides individual neurons with instructions to connect with the correct target neurons in the developing brain.