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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.
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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