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The Journal of Neuroscience, November 26, 2008, 28(48):12969-12981; doi:10.1523/JNEUROSCI.5294-07.2008

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Cellular/Molecular
Polarized Targeting of Neurexins to Synapses Is Regulated by their C-Terminal Sequences

Richard Fairless,¹ Henriette Masius,¹ Astrid Rohlmann,¹ Katharina Heupel,¹ Mohiuddin Ahmad,¹ Carsten Reissner,¹ Thomas Dresbach,² and Markus Missler¹

¹Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, D-48149 Münster, Germany, and ²Institute for Anatomy and Cell Biology II, University of Heidelberg, D-69120 Heidelberg, Germany

Correspondence should be addressed to Prof. Markus Missler, Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, D-48149 Münster, Germany. Email: markus.missler{at}uni-muenster.de

Two families of cell-adhesion molecules, predominantly presynaptic neurexins and postsynaptic neuroligins, are important for the formation and functioning of synapses in the brain, and mutations in several genes encoding these transmembrane proteins have been found in autism patients. However, very little is known about how neurexins are targeted to synapses and which mechanisms regulate this process. Using various epitope-tagged neurexins in primary hippocampal neurons of wild-type and knock-out mice in vitro and in transgenic animals in vivo, we show that neurexins are trafficked throughout neurons via transport vesicles and the plasma membrane insertion of neurexins occurs preferentially in the axonal/synaptic compartment. We also observed that exit of neurexins from the ER/Golgi and correct targeting require their PDZ-binding motif at the C terminus, whereas two presumptive ER retention signals are inactive. The ubiquitous presence of neurexin-positive transport vesicles and absence of bassoon colabeling demonstrate that these carriers are not active zone precursor vesicles, but colocalization with CASK, RIM1, and calcium channels suggests that they may carry additional components of the exocytotic machinery. Our data indicate that neurexins are delivered to synapses by a polarized and regulated targeting process that involves PDZ-domain mediated interactions, suggesting a novel pathway for the distribution of neurexins and other synaptic proteins.

Key words: secretory pathway; PDZ domain; neuroligin; autism; synaptic plasticity; neurotransmission

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Received Aug. 22, 2008; revised Oct. 17, 2008; accepted Oct. 21, 2008.

Correspondence should be addressed to Prof. Markus Missler, Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, Vesaliusweg 2-4, D-48149 Münster, Germany. Email: markus.missler{at}uni-muenster.de

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