SUMMARY Neuromuscular synapse formation requires a complex exchange of signals between motor neurons and skeletal muscle fibers, leading to the accumulation of postsynaptic proteins, including acetylcholine receptors in the muscle membrane and specialized release sites, or active zones in the presynaptic nerve terminal. MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, and Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors are a major cause of a group of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). How Agrin activates MuSK and stimulates synaptic differentiation is not known and remains a fundamental gap in our understanding of signaling at neuromuscular synapses. Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK and mediates MuSK activation by Agrin.

Alternative RNA splicing represents a central mechanism for expanding the coding power of genomes. Individual RNA-binding proteins can control alternative splicing choices in hundreds of RNA transcripts, thereby tuning amounts and functions of large numbers of cellular proteins. We found that the RNA-binding protein SLM2 is essential for functional specification of glutamatergic synapses in the mouse hippocampus. Genome-wide mapping revealed a markedly selective SLM2-dependent splicing program primarily consisting of only a few target messenger RNAs that encode synaptic proteins. Genetic correction of a single SLM2-dependent target exon in the synaptic recognition molecule neurexin-1 was sufficient to rescue synaptic plasticity and behavioral defects in Slm2 knockout mice. These findings uncover a highly selective alternative splicing program that specifies synaptic properties in the central nervous system.

Nervous systems represent remarkable examples of a highly organized tissue with an abundance of specialized cells in an intricate structure. During development, neuronal connectivity arises from a series of steps, including cell specification, migration, targeted growth, synapse formation and remodelling. Spontaneous activity and sensory experience propagated through the developing networks play a significant role in organizing aspects of neuronal wiring. However, many fundamental steps of neuronal morphogenesis and synapse formation proceed normally even in the absence of neurotransmission [1][2][3] . Thus, genetically encoded programmes are thought to orchestrate key aspects of the timing and dynamics of neuronal growth and nervous system wiring [4][5][6][7] . Cell surface adhesion and signalling molecules significantly contribute to all of these developmental steps. Thus, each neuronal cell type carries an array of cues linked to cellular origin and cell fate that are integral to its developmental specification. Although signalling processes, neuronal activity and disease states may shift these codes, there are constraints that restrict this plasticity, thereby maintaining cell type-specific properties. One critical and extensively studied process in nervous system development is the selective growth and targeting of neurites, which encompasses axon guidance and synaptic specificity 7,8 . The present Review aims to discuss a second key aspect of neuronal wiring: the molecular principles of neuronal synapse formation and the specification of synapse function. We will use the Neurexin family, one class of cell adhesion molecules, to illustrate the fundamental principles of this process that likely apply to many other adhesion systems operating at neuronal synapses.Adhesive modules for synapse assembly. Synaptic differentiation relies on a large number of synaptic adhesion and signalling molecules with so-called synaptogenic properties, that is, the ability of an isolated factor to trigger a substantial degree of the synaptic differentiation process. When presented in non-neuronal cells or on synthetic surfaces, synaptogenic proteins nucleate the formation of functional presynaptic or postsynaptic assemblies 9-12 . For example, postsynaptic adhesion molecules of the Neuroligin family trigger the assembly of functional presynaptic terminals in axons through interaction with their receptor Neurexin 9,10 (Fig. 1a). Conversely, Neurexin-mediated clustering of Neuroligins triggers the recruitment of NMDA-type glutamate receptors and scaffolding molecules 12,13 . This early cell biological analysis uncovered fundamental activities of Neurexin proteins and their ligands. Subsequent genetic studies then probed the functional consequences of inactivating Neurexin genes in various model organisms (see below). What makes the roles for Neurexins in this process so fascinating is twofold. First, the Neurexin gene family encodes a vast array of distinct transcript isoforms generated from multiple genes (Nrxn1, Nrxn2, Nrxn3), a...

Highlights d Most mouse Cre driver lines tested exhibited variable rates of germline recombination d Germline recombination exhibits parental sex bias and target locus selectivity d Similar principles apply to multiple organisms and recombinase systems d Guidelines are provided for detecting and minimizing unwanted germline recombination

Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4−/− mice fail to form neuromuscular synapses and die at birth. Lrp4−/− mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. To learn whether synapses form and function aberrantly, we used electrophysiological and anatomical methods to study hippocampal CA3–CA1 synapses. In the absence of Lrp4, the organization of the hippocampus appeared normal, but the frequency of spontaneous release events and spine density on primary apical dendrites were reduced. CA3 input was unable to adequately depolarize CA1 neurons to induce long-term potentiation. Our studies demonstrate a role for Lrp4 in hippocampal function and suggest that patients with mutations in Lrp4 or auto-antibodies to Lrp4 should be evaluated for neurological deficits.DOI: http://dx.doi.org/10.7554/eLife.04287.001