Neural connectivity, the collection of synapses wiring nervous system cells, is a major property of a nervous system, and a determinant of neural function. In humans, billions of neurons make trillions of synapses, and the proper function of this system depends on proper wiring. Incorrect wiring of neurons can lead to improper perception and various neurodevelopmental diseases. While it is generally accepted that the connectivity is determined by cell surface receptors that uniquely label neurons and mechanistically guide their wiring, we know a relatively few number of these receptors. Given the complexity of nervous systems, we need to discover more neural receptors and learn how they function, so as to be able to understand brain development and the physiology of diseases where neural wiring is central. To address this, we are working to reveal the identity and physiological function of cell surface receptors that uniquely label neurons and guide their wiring. Previously, using a biochemical approach (protein interaction screening), we have identified two protein families, Dprs and DIPs in Drosophila, that are determinants of neural connectivity, and are a unique case of an interaction code that likely guides synaptic pairing of neurons in the brain. Members of Dpr and DIP families bind each other not in a simple one-to-one fashion; each Dpr and DIP interacts with many DIPs and Dprs, a phenomenon we call cross-reactivity, and mediates a unique set of interactions. In addition, we have discovered a secreted protein we have named common DIP (cDIP), which binds 21 out of 30 Dprs and DIPs, and likely has a regulatory function on Dpr/DIP-mediated neural connections. Here, we propose to reveal the molecular principles that establish this code, which includes 57 interactions, and study the biology of Dpr/DIP- guided synapse formation in vitro, in culture and in vivo. Our multi-faceted approach includes (1) a biophysical and structural characterization of the Dpr-DIP interactions, followed by engineering of Dprs and DIPs to create novel molecular affinities to be tested for novel neural connectivity in the Drosophila brain; (2) a cellular study of Dpr-DIP mediated adhesions and the effect of the common DIP on these cell adhesions; and (3) the creation of a cell-based system for studying the signaling of Dprs and DIPs via the TGF-?/BMP signaling pathway.
Neural connectivity is altered in many if not most neurodevelopmental disorders. Schizophrenia and autism are both strongly correlated with modified levels of connectivity within the brain. A mechanistic understanding of how the neural circuitry is formed is crucial in understanding how neurodevelopmental disorders emerge. The work proposed here addresses fundamental questions on the principles and mechanisms of neural wiring in a model case, the wiring of the optic lobe, by studying cell surface receptors on neurons. Mechanistic principles learned here may be crucial in developing future therapies that target neural wiring, especially at the level of cell surface receptors, which are the most accessible components of the wiring mechanism.
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