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Dietmar Schmucker,
Harvard Medical School, Department of Neurobiology and Dana-Farber Cancer Institute, Department of Cancer Biology; Boston 02113 MA, USA
The nervous system, like the immune system, needs to generate extraordinary diversity and specificity in molecular recognition. It has been estimated that some 1012 neurons are interconnected by up to 1015 synapses. Surprisingly, the human genome contains fewer than 30,000 genes. How is the relative small amount of genetic information utilized to specify such a complex wiring diagram?
We are interested in finding answers to this challenging question. In general, our goal is to dissect developmental mechanisms that control the formation of specific neuronal circuits. We are using genetic, cell biological, biochemical and structural methods to better understand how the molecular specification of synaptic targets is achieved. In much of our work we are taking advantage of the powerful genetic tools available for the model organism Drosophila melanogaster. However we have recently started to also extend our studies to the analysis of neural circuit formation in vertebrates. We are particularly interested in using the model organism Xenopus tropicalis and combine biochemical, reverse genetic as well as imaging techniques for a dissection of neural circuit formation.
Over the last several years our studies have been focusing on the recognition specificity and signal transduction of membrane receptors of the Immunoglobulin superfamily (Ig-SF). Specifically, we have been studying the function of the Ig-domain containing neuronal receptor “Dscam” in flies. The Drosophila Dscam receptor is closely related to the human protein Down syndrome cell adhesion molecule (DSCAM). Through alternative splicing the Drosophila Dscam gene (but not vertebrate DSCAM) gives rise to thousands of diverse cell surface receptors (~38,000) thought to provide homophilic and possibly heterophilic recognition specificity for neuronal wiring and immune responses.
We are investigating the in vivo role of Dscam’s isoform specificity during neuronal wiring. Genetic studies reveal that reduction of Dscam diversity results in specific wiring defects of complex highly branched sensory neurons. Furthermore, cell-intrinsic functions of Dscam in sensory neurons control complex dendrite morphogenesis. In this context, isoform-specific homophilic interactions of receptors positioned on interacting membrane compartments result in neurite repulsion. Isoform specificity of Dscam provides a form of molecular identity recognition that is used to distinguish self and non-self. We are interested to dissect the molecular mechanisms of such receptor-based identity recognition and investigate whether this novel concept is of general importance for neuronal wiring. |
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