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Peter Scheiffele, Ph.D. Assistant Professor of Physiology & Cellular Biophysics Email: ps2018@columbia.edu Tel: (212) 305-0204 Office: BB1119 Fax:(212) 305-5775 |
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CURRENT RESEARCH MOLECULAR MECHANISMS OF SYNAPSE FORMATION. Molecular Mechanisms of Synapse Formation in the CNS The precision of synaptic connectivity is essential for normal brain function. This becomes evident in various nervous system disorders where synaptic dysfunction or aberrant connectivity lead to disease states. We are investigating the signaling events between pre- and post-synaptic partners that mediate the formation of synapses in CNS neurons. Understanding the molecular mechanism of this process may permit to devise therapeutic strategies to control synaptic connectivity which are of particular importance for the treatment of neurological problems such as spinal cord injuries where severing of synaptic connections leads to paralysis, and for the prevention and therapy of diseases with aberrant synaptic connectivity and function, such as Alzheimer's disease and epilepsy. We are pursuing two complementary approaches to investigate the molecular mechanisms of synaptic differentiation. In one project we are analyzing the gene expression program of synaptic differentiation that provides control over cellular functions on a global level. In the second project we have focused on the cell biological mechanisms that locally control the differentiation of individual pre- and postsynaptic specializations at the cell surface. Functional Genomics Analysis of Synaptic Differentiation We utilized cDNA microarrays to elucidate global patterns of gene expression during development of the mouse cerebellar ponto-cerebellar projection system. Through this analysis we identified groups of genes specific to neuronal precursor cells, associated with axon outgrowth and regulated in response to contact with synaptic targets. To directly isolate genes, which are differentially regulated by target cell contact and synapse formation we monitored gene expression in the pontine nuclei of mutant mice that lack the synaptic target cells for pontine axons. These experiments revealed that the termination of the gene expression program for axon outgrowth does not depend on the presence of specific target cells. The initiation of the synaptic gene expression program, however, was impaired. Using this functional genomics screen we identified 20 genes that are expressed in the presynaptic partner and that are regulated by target cell contact. We are currently performing gain- and loss-of-function experiments for these genes to determine their function in the formation and stabilization of synapses in vitro and in vivo. Initiation of Synaptic Differentiation by Adhesion and Signaling Molecules The initial morphological and functional differentiation of synapses depends on bi-directional signaling mediated through cell surface molecules. Using a functional in vitro assay we have previously characterized a synapse-inducing activity of the post-synaptic transmembrane protein neuroligin. Candidate receptors for neuroligin that may function in the assembly of presynaptic terminals are the neurexins, however, the subcellular localization and function of neurexins has so far remained elusive. In our recent studies we could demonstrate that: i) neurexins are concentrated at synapses, ii) purified neuroligin is sufficient to cluster neurexin and to induce presynaptic differentiation, iii) oligomerization of neuroligin is required for its function, iv) neurexin clustering is sufficient to induce presynaptic differentiation, and v) neurexin activity requires its cytoplasmic domain. We propose a two-step model in which postsynaptic neuroligin multimers initially cluster axonal neurexins. In response to the clustering, neurexins nucleate the assembly of a cytoplasmic scaffold to which the exocytotic apparatus is recruited. Our studies suggest that the formation of synapses and neuronal circuits in the developing CNS is controlled by mechanisms that operate on two levels. Cell surface adhesion and signaling molecules trigger the assembly of pre- and post-synaptic structures, largely by recruiting pre-existing protein complexes and organelles such as active zone components, synaptic vesicles, neurotransmitter receptors, and scaffolding molecules. These locally restricted interactions lead to the assembly of individual synaptic connections. However, these cell-cell interactions also initiate a specific gene expression program in the synaptic partners. The selective up-regulation of specific synaptic components may provide a reinforcement mechanism that stabilizes appropriate synaptic connections during development and provides global control over the synaptic connectivity of a cell. SELECTED PUBLICATIONS Chih, B., Gollan, L., and Scheiffele, P. 2006. Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex. Neuron 51:171-8. view abstract Buttery, P., Beg, A.., Chih, B., Broder, A., Mason, C., Scheiffele, P. 2006. The diacylglycerol-binding protein alpha1-chimaerin regulates dendritic morphology. Proceedings of the National Academy of Sciences of the United States of America 103:1924-9. view abstract Rosales, C., Osborne, K., Zuccarino, G., Scheiffele, P., and Silverman, M. 2005. A cytoplasmic motif targets neuroligin-1 exclusively to dendrites of cultured hippocampal neurons. The European Journal of Neuroscience 22:2381-6. view abstract Chih, B., Engelman, H., and Scheiffele, P. 2005. Control of excitatory and inhibitory synapse formation by neuroligins. Science 307:1324-8. view abstract Washbourne, P., Dityatev, A., Scheiffele, P., Biederer, T., Weiner, J., Christopherson, K., El-Husseini, A., 2004. Cell adhesion molecules in synapse formation. Journal of Neuroscience 24:9244-9. view abstract Kalinovsky, A., Scheiffele, P., 2004. Transcriptional control of synaptic differentiation by retrograde signals. Current Opinion in Neurobiology 14:272-9. view abstract |
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