Nicholas C. Spitzer
e-mail: nspitzer@ucsd.edu |
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What are the mechanisms by which neurons differentiate to achieve the spectacular complexity of the brain? Remarkably, voltage-dependent ion channels and neurotransmitter receptors are expressed at early stages of development, substantially before synapse formation, and ion channel activity participates in signal transduction that directs subsequent steps of development. We have discovered that spontaneous transient elevations of intracellular calcium, generated by ion channels and receptors, control several aspects of differentiation during an early period in embryonic development. Our work is aimed at understanding the roles of electrical activity in assembly of the nervous system, by analyzing the effects of calcium transients on neuronal differentiation and determining the molecular mechanisms by which they exert these effects.
Specification of neurotransmitters and selection of transmitter receptors are processes that depend on patterned spontaneous embryonic calcium-dependent electrical activity. We are investigating the triggers of this spontaneous activity to understand its origins. We are studying activity-dependent regulation of expression of serotonin and dopamine in the embryonic brain, because these transmitters have broad impact on cognitive states and on behavior. We have begun analyzing the signaling mechanisms mediating activity-dependent transmitter specification, generating transgenic lines expressing fluorescent reporters of neurotransmitter synthesis to enable mutant screens. We are determining the extent to which there is environmental regulation of activity-dependent differentiation at early stages of development, revealing a partnership of electrical activity and genetic programs in the assembly of the nervous system.
The frequency of transient elevations of intracellular
calcium in growth cones regulates axon extension in identified
neurons in situ. The image shows the preparation used
to study this phenomenon - exposed nerve projections of an embryonic
Xenopus spinal cord and notochord, double-labeled for
β-tubulin (red)
and actin (green) and visualized by confocal microscopy.
Root, C.M., Velázquez-Ulloa, N.A., Monsalve, G.C., Minakova, E. and Spitzer, N.C. (2008) Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J. Neurosci., in press.
Sann, S.B., Xu, L., Nishimune, H., Sanes, J.R. and Spitzer, N.C. (2008) Neurite outgrowth and in vivo sensory innervation mediated by a CaV2.2 - laminin β2 stop signal. J. Neurosci. 28: 2366-2374.
Borodinsky, L.N. and Spitzer, N.C. (2007) Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction. Proc. Natl. Acad. Sci. 104: 335-340.
Spitzer, N.C. (2006) Electrical activity in early neuronal development. Nature 444: 707-712.
Conklin, M.W., Lin, M.S. and Spitzer, N.C. (2005) Local calcium transients contribute to disappearance of pFAK, focal complex removal and deadhesion of neuronal growth cones and fibroblasts. Dev. Biol. 287: 201-212.
Borodinsky, L.N., Root, C.M., Cronin, J.A., Sann, S.B., Gu, X. and Spitzer, N.C. (2004) Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429: 523-530.
Gorbunova, Y.V. and Spitzer, N.C. (2002). Dynamic interactions of cAMP transients and spontaneous calcium spikes. Nature 418: 93-96.
Gomez, T.M., Robles, E., Poo, M.-m. and Spitzer, N.C. (2001). Filopodial calcium transients promote substrate-dependent growth cone turning. Science 291: 1983-1987.
Watt, S.D., Gu, X., Smith, R.D. and Spitzer, N.C. (2000). Specific frequencies of spontaneous calcium transients upregulate GAD 67 transcripts in embryonic neurons. Molec. Cell. Neurosci 16: 376-387.
Vincent, A., Lautermilch, N.J. and Spitzer, N.C. (2000). Antisense suppression of a potassium channel gene demonstrates its role in maturation of the action potential. J. Neurosci. 20: 6087-6094.
Gomez, T.M. and Spitzer, N.C. (1999). In vivo regulation of axon extension and pathfinding by growth-cone calcium transients. Nature 397: 350-355.
Nick Spitzer received his Ph.D. from Harvard University and was a postdoctoral fellow at Harvard and University College, London. He joined the faculty in 1972 and has been the recipient of a Sloan Fellowship, a Javits Neuroscience Investigator Award and a Guggenheim Fellowship. He is a fellow of the American Association for the Advancement of Science, a member of the American Academy of Arts and Sciences and co-director of the UCSD Kavli Institute for Brain and Mind.
