Mechanisms Regulating Neuronal Phenotype and Behavior

Gail Mandel
Professor
Investigator - Howard Hughes Institute
Ph.D. UCLA

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Fouad Atouf, Postdoctoral Fellow
Nurit Ballas, Postdoctoral Fellow
Elena Battaglioli, Postdoctoral Fellow
Julia Dallman, Postdoctoral Fellow
Julia Grimes, Postdoctoral Fellow
Shin-ichi Higashijima, Postdoctoral Fellow
Dianna Berry, Graduate Student





The ability of excitable cells, such as neurons, to respond on a millisecond time scale to a wide variety of stimuli sets them apart from cells in other tissues. Two families of proteins, ion channels and neurotransmitter receptors, are critical for rapid signaling within and between cells. These proteins are found in the plasma membrane and are expressed in discrete anatomical regions in the central and peripheral nervous systems. Even within a small region of nervous tissue, the expression of a particular ion channel or receptor may be restricted to only type of neuron. In addition to this anatomical specificity, the expression of ion channel and receptor proteins is also under strict temporal control during development. How is such specificity generated and maintained in the animal? To approach this question, we have studied the neural-specific expression of genes encoding several different types of ion
channels and receptors. In the course of this work we discovered that neural-specific expression of a large set of genes essential to the neuronal phenotype is at the transcriptional level. This regulation involves a unique class of repressor molecule that we identified by molecular cloning. The repressor is present only in non-neural cell types. We are currently investigating the molecular mechanisms by which this repressor protein works and how repressor gene expression is confined to non-neural cell types.

We have also begun a new set of studies combining molecular biology, electrophysiology, and optical imaging techniques to dissect the molecular basis of behavior in living animals. These studies make use of the genetics of zebrafish and the well characterized neuronal circuitry underlying certain types of behavior. In one set of experiments, for example, we will test whether signaling molecules such as kinases and phosphatases change intracellular
compartments in individual neurons that are firing during a specific behavior. These new studies are being performed in collaboration with Drs. Paul Brehm and Joseph Fetcho, faculty members in the Department of Neurobiology & Behavior at Stony Brook.

Selected Publications:

Chong, J. A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J.J., Zheng, Y., Boutros, M. C., Altshuller, Y. M., Frohman, M.A., Kraner, S. D., and Mandel, G. (1995) REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80: 949-957.

Tapia-Ramirez J., Eggen, B.J.L., Peral-Rubio, M. J., Toledo-Aral, J. J., and Mandel, G. (1997) A single Zinc Finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter. Proc. Natl. Acad. Sci USA 94:1177-1182.

Goodman R. H. and Mandel G. (1998) Off-and-on relationships in the Nervous System. Current Opinion in Neurobiology. Volume 8/3 In Press.