Our group is interested in the molecular mechanisms that regulate synapse formation in the mammalian central nervous system.

Synapses are asymmetric cell-cell contacts, typically formed between the presynaptic axon terminal of a 'sending' nerve cell and the postsynaptic dendrite, the soma or - in some cases - the axon of a 'receiving' one. The presynaptic axon terminal is specialized for the complex membrane trafficking mechanisms that underlie regulated secretion of neurotransmitter, while the postsynapse is uniquely specialized for signal transduction. Synaptogenesis, the formation of functional synapses, is the final step in the development of the central nervous system. In the mammalian brain, it results in the establishment of a neural network, connecting some 1012 nerve cells with up to 1015 synapses. In principle, synaptogenesis takes place in two consecutive steps that are most likely mediated by cell adhesion molecules. First, an arriving axonal growth cone identifies its appropriate partner cell, creating an initial contact, and second, specific axonal and dendritic protein components are recruited to this initial contact site, forming a functional synapse.

Using morphological, biochemical, and mouse genetic approaches, we are studying the role of Neuroligins in synaptogenesis. Neuroligins are Type 1 transmembrane proteins. In mammals, three Neuroligin isoforms are expressed (Neuroligins 1,2,3). Neuroligin 1 is specifically localised to synaptic junctions (Song et al., 1999; Figure 1). Neuroligins are thought to form a transsynaptic cell adhesion system with presynaptic beta-Neurexins (Figure 2). During synaptogensis, this transsynaptic contact is thought to be important for the recruitment of pre- and postsynaptic proteins to initial synaptic contacts (Brose, 1999).

In the project funded by SFB 271, we are examining the role of HECT-type ubiquitin ligases in the regulation of Neuroligin-mediated cell adhesion. We identified the ubiquitin ligase Nedd4 as a novel interaction partner for the intracellular C-termini of Neuroligins 1 and 2. Current research focuses on the biochemical and cell biological characterisation of Neuroligin ubiquitination by Nedd4 and its possible role in synapse elimination during development.

References

Brose, N. (1999) Synaptic cell adhesion proteins and synaptogenesis in the mammalian central nervous system. Naturwissenschaften 86, 516-524.

Song, J., Ichtchenko, K., Sudhof, T.C. und Brose, N. (1999) Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc. Natl. Acad. Sci. U.S.A. 96, 1100-1105.

Legends

Figure 1

Neuroligin 1 is localised to synaptic junctions. Antibodies to the extracellular region of Neuroligin 1 (detected with secondary antibodies coupled to gold particles) detect Neuroligin 1 in the synaptic cleft. Note the presence of three gold particels in the synaptic cleft (left). The diagram on the right depicts the underlying structure whose conservation is poor under the fixation conditions used here.

Figure 2

The Neuroligin/beta-Neurexin-junction is the core of a newly forming synapse. Postsynaptic Neuroligin interacts with presynaptic beta-Neurexin to form a transsynaptic cell-adhesion complex at a developing synapse. Once the junction is formed, Neuroligins and beta-Neurexins initiate well characterized intracellular protein-protein-interaction cascades. These lead to the recruitment of proteins of the transmitter release machinery on the presynaptic side and of signal transduction proteins on the postsynaptic side. The resulting transsynaptic link could also function in retrograde and anterograde signalling of mature synapses. CASK and Mint 1 are presynaptic PDZ-domain proteins with a scaffold function; Munc18 and syntaxin are essential components of the presynaptic transmitter release machinery; PSD95, PSD93, SAP102, and S-SCAM are postsynaptic PDZ-domain proteins with a scaffold and assembly function that recruit ion channels (e.g. K+-channels), neurotransmitter receptors (e.g. NMDA receptors) and other signal transduction proteins (GKAP, SynGAP, CRIPT).