George J. Zanazzi
B.S. Stanford University, 1993
Ph.D. Neuroscience, 2011

4th Year Medical Student

Advisor: Gary Matthews, Ph.D.

Department: Neurobiology & Behavior

Graduate Program: Neuroscience

Title:  Targeting and roles of complexins in zebrafish ribbon-containing neurons

Abstract:

          The primary receptor cells of the visual, auditory, vestibular and lateral line systems encode a broad range of sensory information by modulating the tonic release of the neurotransmitter glutamate in response to graded changes in membrane potential. The output synapses of these neurons are marked by structures called synaptic ribbons, which tether a pool of releasable synaptic vesicles at the active zone. Despite the importance of the ribbon in synaptic transmission, the molecular mechanisms that govern the assembly and function of the exocytotic machinery in these terminals are poorly understood. We have identified a subfamily of SNARE complex regulators, composed of complexin 3 and complexin 4, which are enriched in ribbon-containing sensory neurons. Phylogenetic analysis reveals that there are two complexin 3 paralogs and three complexin 4 paralogs in zebrafish. Complexin 3/4 is rapidly targeted to photoreceptor presynaptic terminals in the zebrafish retina and pineal organ concomitantly with RIBEYE, a member of the CtBP family of transcriptional corepressors that is the major component of ribbons. In hair cells of the inner ear and lateral line, however, complexin 3/4 immunoreactivity clusters on the apical surfaces of hair cells, among their stereocilia. While a complexin 4a-specific antibody and riboprobe selectively label visual system ribbon-containing neurons, neuromasts and the inner ear contain complexin 4b. Complexin 4a knockdown in vivo perturbs visual background adaptation and optokinetic responses, indicating that these mutants are blind, without grossly affecting photoreceptor presynaptic architecture. Complexins may have additional functions during development since modulation of complexin 3a levels via knockdown or overexpression induces pleiotropic effects on dorsoventral patterning and eye development. Taken together, these results provide evidence for the concurrent transport and/or assembly of multiple components of the active zone in developing ribbon terminals. Members of the complexin 3/4 subfamily are enriched in these terminals in the visual system and in hair bundles of the octavolateral system, suggesting that these proteins are differentially targeted and have multiple roles in ribbon-containing sensory neurons. Furthermore, these results implicate complexin 3 and complexin 4 as candidate genes for hereditary visual, auditory, and vestibular disorders.

Publications:
(pre-MSTP publications indicated with an *)

Nayar, S., *Zanazzi, G., Harth, C. 2012. Reversible cerebral vasoconstriction syndrome associated with subarachnoid hemorrhage in a woman with torticollis. In preparation.

Vaithianathan, T., *Zanazzi, G., Akmentin, W., Matthews, G. 2012. Stabilization of spontaneous neurotransmitter release at ribbon synapses by ribbon-specific subtypes of complexin. Submitted.

Zanazzi, G., Matthews, G. 2010. Enrichment and differential targeting of complexins 3 and 4 in ribbon-containing sensory neurons during zebrafish development. Neural Dev. Sep 1;5:24.

Zanazzi, G., Matthews, G. 2009. The molecular architecture of ribbon presynaptic terminals. Mol. Neurobiol. 39:130-148.

Zanazzi, G., Matthews, G. 2007. A doubleheader in endocytosis. Neuron. 56:939-942.

*Koticha, D., Maurel, P., Zanazzi, G., Kane-Goldsmith, N., Basak, S., Babiarz, J., Salzer, J., and Grumet, M. 2006. Neurofascin interactions play a critical role in clustering sodium channels, ankyrin G and beta IV spectrin at peripheral nodes of Ranvier. Devel. Biol. 293:1-12.

*Taveggia C., Zanazzi, G., Petrylak, A., Yano, H., Rosenbluth, J., Einheber, S., Xu, X., Esper, R., Loeb, J., Shrager, P., Falls, D.L., Chao, M.V., Role, L., and Salzer, J.L. 2005. Type III neuregulin-1 levels determine the ensheathment fate of axons. Neuron. 47:681-694.

*Melendez-Vasquez, C., Carey, D.J., Zanazzi, G., Reizes, O., Maurel P., and Salzer, J.L. 2005. Differential expression of proteoglycans at central and peripheral nodes of Ranvier. Glia. 52:301-308.

*Gil, O.D., Zhang, L., Chen, S., Ren, Y.Q., Pimenta, A., Zanazzi, G., Hillman, D., Levitt, P. and Salzer, J.L. 2002. Complementary expression and heterophilic interactions between IgLON family members neurotrimin and LAMP. J. Neurobiol. 51:190-204.

*Rambukkana, A., Zanazzi, G., Tapinos, N. and Salzer, J.L. 2002. Contact-dependent induction of demyelination by Mycobacterium leprae in the absence of immune cells. Science. 296:927-931.

*Chen, S., Gil, O.D., Ren, Y.Q., Zanazzi, G., Salzer, J.L. and Hillman, D. 2002. Neurotrimin expression during cerebellar development suggests roles in axon fasciculation and synaptogenesis. J. Neurocytol. 30:927-937.

*Lustig M.*, Zanazzi G.*, Sakurai T., Blanco C., Levinson S.R., Lambert S., Grumet M., and Salzer J.L. 2001. Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier. Curr. Biol. 11:1864-1869. *Equal contribution.

*Melendez-Vasquez, C., Rios, J.C., Zanazzi, G., Bretscher, A., Lambert, S. and Salzer, J.L. 2001. Nodes of Ranvier form in association with ERM-positive Schwann cell microvilli. Proc. Natl. Acad. Sci. 98:1235-1240.

*Zanazzi, G., Einheber, S., Westreich, R., Hannocks, M.-J., Bedell-Hogan, D., Marchionni, M.A. and Salzer, J.L. 2001. Glial growth factor/neuregulin inhibits myelination and induces demyelination. J. Cell Biol. 152:1289-1299.

*Ng, V.*, Zanazzi, G.*, Timpl, R., Talts, I.F., Salzer, J.L., Brennan, P.J. and Rambukkana, A. 2000. Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell. 103:511-524. *Equal contribution.

*Tikoo, R., Zanazzi, G., Shiffman, D., Salzer, J. and Chao, M.V. 2000. Cell cycle control of Schwann cell proliferation: role of cyclin-dependent kinase-2. J. Neurosci. 20:4627-4634.

*Ching, W., Zanazzi, G., Levinson, S.R. and Salzer, J.L. 1999. Clustering of neuronal sodium channels requires contact with myelinating Schwann cells. J. Neurocytol. 28:295-301.

*Galbiati, F., Volonte, D., Gil, O., Zanazzi, G., Salzer, J.L., Sargiacomo, M., Scherer, P.E., Engelman, J.A., Schlegel, A., Parenti, M., Okamoto, T. and Lisanti, M.P. 1998. Expression of caveolin-1 and -2 in differentiating PC12 cells and dorsal root ganglion neurons: caveolin-2 is up-regulated in response to cell injury. Proc. Natl. Acad. Sci. 95:10257-10262.

*Rambukkana, A., Yamada, H., Zanazzi, G., Mathus, T., Salzer, J.L., Yurchenco, P.D., Campbell, K.P. and Fischetti, V.A. 1998. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science. 282:2076-2079.

*Gil, O.D., Zanazzi, G., Struyk, A. and Salzer, J.L. 1998. Neurotrimin mediates bifunctional effects on neurite outgrowth via homophilic and heterophilic interactions. J. Neurosci. 18:9312-9325.

*Einheber, S., Zanazzi, G., Ching, W., Scherer, S., Milner, T.A., Peles, E. and Salzer, J.L. 1997. The axonal membrane protein Caspr/neurexin IV is a component of the septate-like paranodal junctions that assemble during myelination. J. Cell Biol. 139:1495-1506.

*Desser, T.S., Rubin, D.L., Muller, H.H., Qing, F., Khodor, S., Zanazzi, G., Young, S.W., Ladd, D.L., Wellons, J.A., Kellar, K.E., Toner, J.L. and Snow, R.A. 1994. Dynamics of tumor imaging with Gd-DTPA-polyethylene glycol polymers: dependence on molecular weight. J. Mag. Res. Imag. 4:467-472.

*Young, S.W., Sidhu, M.K., Qing, F., Muller, H.H., Neuder, M., Zanazzi, G., Mody, T.D., Hemmi, G., Dow, W., Mutch, J.D., Sessler, J.L. and Miller R.A. 1994. Preclinical evaluation of gadolinium (III) texaphyrin complex: a new paramagnetic contrast agent for magnetic resonance imaging. Invest. Radiol. 29:330-338.

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