B.S. Stanford University, 1993
Ph.D. Neuroscience, 2011
4th Year Medical Student
Gary Matthews, Ph.D.
Department: Neurobiology & Behavior
Graduate Program: Neuroscience
Targeting and roles of complexins in zebrafish ribbon-containing
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.
(pre-MSTP publications indicated with an *)
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.
G., Matthews, G. 2009. The molecular architecture of ribbon
presynaptic terminals. Mol. Neurobiol. 39:130-148.
G., Matthews, G. 2007. A doubleheader in endocytosis. Neuron.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.