Functional roles of LI-CAM/neuroglian in the nervous system of Drosophila melanogaster

Neuronal cell adhesion molecules of L1 family play a critical role in proper nervous system development. Various mutations on human L1-CAM that lead to severe neurodevelopmental disorders like retardation, spasticity etc. termed under L1 syndrome. The vertebrate L1CAM and its homolog in Drosophila, neuroglian (nrg) have been well studied for their roles in axon pathfinding, neurite extension and cell migration, however, much less is known about the mechanisms by which they fine tune synaptic connectivity to control the development and maintenance of synaptic connections within neuronal circuits. Here we characterized the essential role of nrg in regulating synaptic structure and function in vivo in a well characterized Drosophila central synapse model neuron, the Giant Fiber (GF) system. Previous studies from our lab revealed that the phosphorylation status of the tyrosine in the Ankyrin binding FIGQY motif in the intracellular domain of Nrg is crucial for synapse formation of the GF to Tergo-Trochanteral Motor neuron (TTMn) synapse in the GF circuit.;The present work provided us with novel insights into the role of Nrg-Ank interaction in regulating Nrg function during synapse formation and maintenance. By utilizing a sophisticated Pacman based genomic rescue strategy we have shown that dynamic regulation of the Neuroglian--Ankyrin interaction is required to coordinate transsynaptic development in the GF--TTMn synapse. In contrast, the strength of Ankyrin binding directly controls the balance between synapse formation and maintenance at the NMJ.;Human L1 pathological mutations affect different biological processes distinctively and thus their proper characterization in vivo is essential to understand L1CAM function. By utilizing nrg14;P[nrg180 DeltaFIGQY] mutants that have exclusive synaptic defects and the previously characterized nrg849 allele that affected both GF guidance and synaptic function, we were able to analyze pathological L1CAM missense mutations with respect to their effects on guidance and synapse formation in vivo. We found that 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 and not for axon guidance while L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila.