A Conserved Role for Drosophila Neuroglian and Human L1-CAM in Central-Synapse Formation

Department of Biology, Morrill Science Center, University of Massachusetts, Amherst, Amherst, Massachusetts 01003, USA.
Current Biology (Impact Factor: 9.57). 02/2006; 16(1):12-23. DOI: 10.1016/j.cub.2005.11.062
Source: PubMed


Drosophila Neuroglian (Nrg) and its vertebrate homolog L1-CAM are cell-adhesion molecules (CAM) that have been well studied in early developmental processes. Mutations in the human gene result in a broad spectrum of phenotypes (the CRASH-syndrome) that include devastating neurological disorders such as spasticity and mental retardation. Although the role of L1-CAMs in neurite extension and axon pathfinding has been extensively studied, much less is known about their role in synapse formation.
We found that a single extracellular missense mutation in nrg(849) mutants disrupted the physiological function of a central synapse in Drosophila. The identified giant neuron in nrg(849) mutants made a synaptic terminal on the appropriate target, but ultrastructural analysis revealed in the synaptic terminal a dramatic microtubule reduction, which was likely to be the cause for disrupted active zones. Our results reveal that tyrosine phosphorylation of the intracellular ankyrin binding motif was reduced in mutants, and cell-autonomous rescue experiments demonstrated the indispensability of this tyrosine in giant-synapse formation. We also show that this function in giant-synapse formation was conserved in human L1-CAM but neither in human L1-CAM with a pathological missense mutation nor in two isoforms of the paralogs NrCAM and Neurofascin.
We conclude that Nrg has a function in synapse formation by organizing microtubules in the synaptic terminal. This novel synaptic function is conserved in human L1-CAM but is not common to all L1-type proteins. Finally, our findings suggest that some aspects of L1-CAM-related neurological disorders in humans may result from a disruption in synapse formation rather than in axon pathfinding.

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Available from: Tanja Godenschwege
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    • "However, in this scenario the H210Q and R184Q mutations disrupt outside-in signaling processes via the FIGQY motif. The latter hypothesis is supported by our finding that the nrg849 mutants with the analogous L1-H210Q mutation have reduced tyrosine phosphorylation of the FIGQY motif and synaptic phenotypes similar to nrg14;P[nrg180ΔFIGQY] mutants in addition to guidance defects [6]. Finally, we found that L1-Y1070C mutant protein failed to rescue the synaptic defects of nrg14;P[nrg180ΔFIGQY] mutant flies although its homophilic interactions are not affected by the mutation [15], [32]. "
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    ABSTRACT: A large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and synapse formation and the phenotypes of nrg mutants can be rescued by the expression of human L1CAM. We previously showed that the highly conserved intracellular FIGQY Ankyrin-binding motif is required for L1CAM-mediated synapse formation, but not for neurite outgrowth or axon guidance of the Drosophila giant fiber (GF) neuron. Here, we use the GF as a model neuron to characterize the pathogenic L120V, Y1070C, C264Y, H210Q, E309K and R184Q extracellular L1CAM missense mutations and a L1CAM protein with a disrupted ezrin-moesin-radixin (ERM) binding site to investigate the signaling requirements for neuronal development. We report that different L1CAM mutations have distinct effects on axon guidance and synapse formation. Furthermore, L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila. In addition, the human pathological H210Q, R184Q and Y1070C, but not the E309K and L120V L1CAM mutations affect outside-in signaling via the FIGQY Ankyrin binding domain which is required for synapse formation. Thus, the pathological phenotypes observed in humans are likely to be caused by the disruption of signaling required for both, guidance and synaptogenesis.
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    • "L1 is such a neural CAM of the Ig superfamily. It is widely expressed in the nervous system and is important in axonal outgrowth, guidance, and fasciculation (Burden-Gully et al. 1997; Castellani et al. 2000; Kamiguchi 2003; Whittard et al. 2006; Chen et al. 2007), synapse formation (Godenschwege et al. 2006), and signaling (Panicker et al. 2003). Exogenously applied L1 enhances the growth of neuronal axons in vitro (e.g., Chen and Charness 2012) while cells expressing L1 have been found to promote spinal cord regeneration (He et al. 2012). "
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    ABSTRACT: L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is widely expressed in the nervous system and important in axonal outgrowth, guidance, synapse formation, and signaling. Gene deletion studies emphasize the significance of L1 during development of the central nervous system and L1 is crucial for the topographic targeting of retinal axons. In contrast to the brain and retina, the role of L1 in the inner ear is largely unknown. While previous studies have localized L1 in the developing inner ear of the chicken and mouse, its function during the innervation of the cochlea still remains largely unclear. We therefore investigated the functional role of L1 in the mammalian inner ear. Our aim was to determine whether or not L1 can modulate type I and/or type II spiral ganglion neuron outgrowth using an in vitro alternate choice assay. We found that L1, presented in stripe micropatterns, provide directional cues to neonatal rodent type I but not type II inner ear spiral ganglion neurites. The results suggest that L1 may play a role in axonal pathfinding of type I spiral ganglion dendrites toward their inner hair cell targets but not of type II toward the outer hair cells.
    Full-text · Article · Jun 2013 · Journal of Molecular Neuroscience
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    • "L1CAM behaves as an adhesion molecule in cell-aggregation assays. However L1CAM is more than a specific glue and serves as well as an activator of intracellular signaling pathways [1], [2], [3], [4]. L1CAM couples the highly specific recognition interaction mediated by homophilic adhesion with the activation of the EGFR (also known as erbB1). "
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    ABSTRACT: During nervous system development different cell-to-cell communication mechanisms operate in parallel guiding migrating neurons and growing axons to generate complex arrays of neural circuits. How such a system works in coordination is not well understood. Cross-regulatory interactions between different signalling pathways and redundancy between them can increase precision and fidelity of guidance systems. Immunoglobulin superfamily proteins of the NCAM and L1 families couple specific substrate recognition and cell adhesion with the activation of receptor tyrosine kinases. Thus it has been shown that L1CAM-mediated cell adhesion promotes the activation of the EGFR (erbB1) from Drosophila to humans. Here we explore the specificity of the molecular interaction between L1CAM and the erbB receptor family. We show that L1CAM binds physically erbB receptors in both heterologous systems and the mammalian developing brain. Different Ig-like domains located in the extracellular part of L1CAM can support this interaction. Interestingly, binding of L1CAM to erbB enhances its response to neuregulins. During development this may synergize with the activation of erbB receptors through L1CAM homophilic interactions, conferring diffusible neuregulins specificity for cells or axons that interact with the substrate through L1CAM.
    Full-text · Article · Jul 2012 · PLoS ONE
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