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J. Biol. Chem., Vol. 281, Issue 9, 6038-6047, March 3, 2006

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Assembly of Active Zone Precursor Vesicles

OBLIGATORY TRAFFICKING OF PRESYNAPTIC CYTOMATRIX PROTEINS BASSOON AND PICCOLO VIA A TRANS-GOLGI COMPARTMENT^*

Thomas Dresbach¹, Viviana Torres^¶2, Nina Wittenmayer, Wilko D. Altrock, Pedro Zamorano^¶2, Werner Zuschratter, Ralph Nawrotzki, Noam E. Ziv^||, Craig C. Garner^¶, and Eckart D. Gundelfinger³

From the Leibniz Institute for Neurobiology, Brenneckestr. 6, D-39118 Magdeburg, Germany, Institute for Anatomy and Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany, ^¶Department of Psychiatry and Behavioral Science, Stanford University, Palo Alto, California 94304-5485, and ^||Department of Physiology, Technion Faculty of Medicine, POB 9649 Bat Galim, Haifa 31096, Israel

Neurotransmitter release from presynaptic nerve terminals is restricted to specialized areas of the plasma membrane, so-called active zones. Active zones are characterized by a network of cytoplasmic scaffolding proteins involved in active zone generation and synaptic transmission. To analyze the modes of biogenesis of this cytomatrix, we asked how Bassoon and Piccolo, two prototypic active zone cytomatrix molecules, are delivered to nascent synapses. Although these proteins may be transported via vesicles, little is known about the importance of a vesicular pathway and about molecular determinants of cytomatrix molecule trafficking. We found that Bassoon and Piccolo co-localize with markers of the trans-Golgi network in cultured neurons. Impairing vesicle exit from the Golgi complex, either using brefeldin A, recombinant proteins, or a low temperature block, prevented transport of Bassoon out of the soma. Deleting a newly identified Golgi-binding region of Bassoon impaired subcellular targeting of recombinant Bassoon. Overexpressing this region to specifically block Golgi binding of the endogenous protein reduced the concentration of Bassoon at synapses. These results suggest that, during the period of bulk synaptogenesis, a primordial cytomatrix assembles in a trans-Golgi compartment. They further indicate that transport via Golgi-derived vesicles is essential for delivery of cytomatrix proteins to the synapse. Paradigmatically this establishes Golgi transit as an obligatory step for subcellular trafficking of distinct cytoplasmic scaffolding proteins.

Received for publication, August 9, 2005 , and in revised form, December 16, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant DR 373/3-1, SFB 426 (to T. D., N. E. Z., and E. D. G.); the German-Israeli Foundation (to N. E. Z. and E. D. G.); National Institutes of Health Grants P50 HD32901, AG 12978-02, AG 06569-09, and P30 HD38985-03 (to C. C. G); and the Fonds der Chemischen Industrie, Alexander von Humboldt Foundation, and the Max Planck Society (to E. D. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

² Present address: Facultad Ciencias de la Salud, Universidad de Antofagasta, Antofagasta 170, Chile.

¹To whom correspondence may be addressed: Inst. for Anatomy and Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany. Tel.: 49-6221-548659; Fax: 49-6221-544952; E-mail: thomas.dresbach{at}urz.uni-heidelberg.de. ³To whom correspondence may be addressed: Leibniz Inst. for Neurobiology, Dept. of Neurochemistry and Molecular Biology, Brenneckestr. 6, D-39118 Magdeburg, Germany. Tel.: 49-391-6263-228; Fax: 49-391-6263-229; E-mail: gundelfinger{at}ifn-magdeburg.de.

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