Leucine-rich repeat transmembrane neuronal proteins...
Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) are a small family of neuronal surface proteins. Their role in the nervous system remained fairly obscure until three studies published last year raised interest in these proteins. First, the lab of Ann Marie Craig at the University of British Columbia identified LRRTMs as synapse-promoting molecules in cell culture (Linhoff et al., 2009). Then, two papers from the lab of Thomas Südhof at Stanford University and the lab of Anirvan Ghosh at the University of California, San Diego, showed that LRRTMs mediate their effects on synapse formation through binding to presynaptic neurexins (de Wit et al., 2009; Ko et al., 2009). This finding came as a surprise, since neurexins, which have been implicated in schizophrenia and autism spectrum disorders, were previously known as the binding partners for the post-synaptic adhesion molecule, neuroligin. A new study from the lab of Ann Marie Craig now extends these findings.
Using an independent approach, Siddiqui and colleagues also identify neurexins as binding partners for LRRTM2 by screening a large number of presynaptic candidate molecules for binding to LRRTM2 (Siddiqui et al., 2010). The authors further confirm previous findings by the Südhof lab that neurexin binding to LRRTM2 is regulated by alternative splicing of neurexins: only those neurexin molecules that lack a small insert in the extracellular domain termed SS#4 can bind to LRRTM2. In contrast, neuroligins bind neurexins regardless of the presence or absence of SS#4, suggesting that neurexins bind LRRTMs and neuroligins with a different code.
The authors then asked which part of neurexin is required for binding to neuroligin and LRRTM2. Surprisingly, they found that both molecules, although structurally very different, interact with a largely overlapping binding surface of neurexin. This raised the possibility that the two synapse-promoting adhesion molecules might compete for binding to neurexin. Binding assays revealed that this was indeed true. To begin to address the role of having multiple adhesion molecules at the synapse, the authors overexpressed neuroligin and LRRTM2 in cultured hippocampal neurons, alone or in combination. It turns out that in concert, these molecules are more effective promoters of synapse formation than individually, suggesting that they might cooperate to regulate synapse development.
These new findings further point to neurexins as key organizers of synapse development through binding to multiple post-synaptic adhesion molecules. One of the main outstanding questions is the role of multiple adhesion molecules at the synapse. This may simply be a matter of redundancy to ensure reliable synapse formation, but it could also be that neuroligins and LRRTMs serve different roles, recruiting different components of the synaptic machinery or regulating different stages of synapse formation. The fact that mutations in neurexins, LRRTMs, and neuroligins have all been implicated in autism spectrum disorders and schizophrenia strongly suggests that abnormalities in synapse development underlie these neurological disorders. Understanding the role of these synaptic adhesion proteins in synapse formation and neural circuit formation will therefore be essential for gaining insight into the underlying mechanisms of these devastating disorders.
de Wit, J., Sylwestrak, E., O'Sullivan, M. L., Otto, S., Tiglio, K., Savas, J. N., Yates, J. R., 3rd, Comoletti, D., Taylor, P., and Ghosh, A. (2009). LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 64, 799-806. Abstract
Ko, J., Fuccillo, M. V., Malenka, R. C., and Sudhof, T. C. (2009a). LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron 64, 791-798. Abstract
Linhoff, M. W., Lauren, J., Cassidy, R. M., Dobie, F. A., Takahashi, H., Nygaard, H. B., Airaksinen, M. S., Strittmatter, S. M., and Craig, A. M. (2009). An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 61, 734-749. Abstract
Siddiqui, T. J., Pancaroglu, R., Kang, Y., Rooyakkers, A., and Craig, A. M. (2010). LRRTMs and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development. J Neurosci 30, 7495-7506. Abstract