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 system function relies on complex assemblies of distinct neuronal cell types with unique anatomical and functional properties instructed by molecular programs. Alternative splicing is a key mechanism for the expansion of molecular repertoires and protein splice isoforms shape neuronal cell surface recognition and function. However, the logic of how alternative splicing programs are arrayed across neuronal cells types is poorly understood. We systematically mapped ribosome-associated transcript isoforms in genetically-defined neuron types of the mouse forebrain. Our dataset provides an extensive resource of transcript diversity across major neuron classes. We find that neuronal transcript isoform profiles reliably distinguish even closely-related classes of pyramidal cells and inhibitory interneurons in the mouse hippocampus and neocortex. These highly specific alternative splicing programs selectively control synaptic proteins and intrinsic neuronal properties. Thus, transcript diversification by alternative splicing is a central mechanism for the functional specification of neuronal cell types and circuits.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

In animal locomotion a tradeoff exists between stereotypy and flexibility: fast long-distance travelling (LDT) requires coherent regular motions, while local sampling and area-restricted search (ARS) rely on flexible movements. We report here on a posture control system in C. elegans that coordinates these needs. Using quantitative posture analysis we explain worm locomotion as a composite of two modes: regular undulations versus flexible turning. Graded reciprocal regulation of both modes allows animals to flexibly adapt their locomotion strategy under sensory stimulation along a spectrum ranging from LDT to ARS. Using genetics and functional imaging of neural activity we characterize the counteracting interneurons AVK and DVA that utilize FLP-1 and NLP-12 neuropeptides to control both motor modes. Gradual regulation of behaviors via this system is required for spatial navigation during chemotaxis. This work shows how a nervous system controls simple elementary features of posture to generate complex movements for goal-directed locomotion strategies.DOI: http://dx.doi.org/10.7554/eLife.14116.001

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...