Cerebellins meet neurexins (Commentary on Matsuda & Yuzaki)
Version of Record online: 17 APR 2011
© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 33, Issue 8, pages 1445–1446, April 2011
How to Cite
Martinelli, D. C. and Südhof, T. C. (2011), Cerebellins meet neurexins (Commentary on Matsuda & Yuzaki). European Journal of Neuroscience, 33: 1445–1446. doi: 10.1111/j.1460-9568.2011.07665.x
- Issue online: 17 APR 2011
- Version of Record online: 17 APR 2011
How synapses are formed and maintained is a fundamental question in neuroscience that is assuming increasing importance for our understanding of numerous neurological disorders. Recently, proteins containing complement factor C1Q-related domains (C1q-domains) have been attracting interest because of their potential role in synapse formation and/or maintenance. C1q-domains are small globular domains found in the eponymous complement factor C1Q and in a multitude of other proteins, including both small secreted proteins such as cerebellins and C1ql proteins, and large multidomain proteins such as emilins and multimerins (Ghai et al., 2007). Accumulating evidence is now implicating several C1q-domain proteins in synapse formation and/or elimination: cerebellin-1 was revealed to function in synapse maturation (Yuzaki, 2009) (Hirai et al., 2005), complement factor C1Q was implicated in synapse elimination (Stevens et al., 2007), and members of a third C1q-domain protein family, C1qls (for C1q-like), were demonstrated to reduce synapse numbers in cultured neurons (Bolliger et al., 2011). New data now published in this issue of EJN (Matsuda and Yuzaki, 2011), complementing earlier reports published in Cell and Science (Matsuda et al., 2010; Uemura et al., 2010), reveal that cerebellin-1 functions in synapse formation by binding to the presynaptic cell-adhesion neurexin molecules, and that other cerebellin isoforms may also do so.
Cerebellin-1 is secreted from cerebellar granule cells, and acts as a ligand for the postsynaptic glutamate receptor (GluR)δ2 on Purkinje cells (Matsuda et al., 2010). Cerebellin-1 additionally binds to presynaptic neurexin-1β, resulting in a trimeric trans-synaptic complex composed of cerebellin-1, GluRδ2, and neurexin-1β (Uemura et al., 2010). In the present EJN article, Matsuda and Yuzaki use cell-based binding assays to demonstrate that cerebellin-1 also binds to neurexin-1α, as well as to all three β-neurexins. This binding interaction requires the inclusion of an alternatively spliced exon known as ‘splice site #4’ (Ushkaryov et al., 1992), and appears to be Ca2+-independent. The cerebellin-1 binding properties for neurexins are thus distinct from those of neuroligins (Ichtchenko et al., 1995) or LRRTMs (Ko et al., 2009; de Wit et al., 2009). This result suggests that alternative splicing of neurexins at splice site #4 influences whether they bind to either cerebellin-1 or to neuroligins and LRRTM2.
Matsuda and Yuzaki further demonstrate that cerebellin-2 (but, interestingly, not cerebellin-4) also binds to neurexin-1β. The authors provide evidence that cerebellin-1 and cerebellin-2 have similar synaptogenic activities in cultured hippocampal and cortical neurons, not just in cerebellar neurons. Thus, the new article provides further evidence that cerebellin-1 acts as a bi-directional synapse organizer, initiating the recruitment of both presynaptic and postsynaptic proteins to the points of contact with both neurexin-1β and GluRδ2.
The picture of cerebellins emerging from these studies suggests that they function as ‘connectors’, linking presynaptic neurexins to postsynaptic GluRδ-type receptors, and that, in doing so, they activate synapse formation. This attractive hypothesis raises a slew of new questions. For example, what is the mechanism by which such binding activates synapse formation – possibly by multimerization of the binding partners – and does this binding initiate synapse formation, or stabilize transient synapses established by other mechanisms? On a higher level, these results raise the questions of whether cerebellin binding is the primary function of neurexin proteins containing splice site #4, how important such binding is for the formation of brain circuits, and whether other postsynaptic cerebellin receptors exist. Answers to these questions will yield a greater understanding of how synapses are formed and maintained in the cerebellum and the numerous other brain regions where cerebellin family members are expressed.
- 2011) The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins. Proc. Natl Acad. Sci. USA, 108, 2534–2539. , & (
- 2007) C1q and its growing family. Immunobiology, 212, 253–266. , , , , , , & (
- 2005) Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat. Neurosci., 8, 1534–1541. , , , , , , , , , & (
- 1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell, 81, 435–443. , , , , , & (
- 2009) LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron, 64, 791–798. , , & (
- 2011) Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions. Eur. J. Neurosci., 33, 1447–1461. & (
- 2010) Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science, 328, 363–368. , , , , , , , , , , & (
- 2007) The classical complement cascade mediates CNS synapse elimination. Cell, 131, 1164–1178. , , , , , , , , , , , , , , & (
- 2010) Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell, 141, 1068–1079. , , , , , , , & (
- 1992) Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. Science, 257, 50–56. , , & (
- 2009) LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron, 64, 799–806. , , , , , , , , & (
- 2009) New (but old) molecules regulating synapse integrity and plasticity: Cbln1 and the delta2 glutamate receptor. Neuroscience, 162, 633–643. (