A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Godenschwege
Tanja A
TA
Department of Biology, Morrill Science Center, University of Massachusetts, Amherst, Amherst, Massachusetts 01003, USA. tanjag@bio.umass.edu
Kristiansen
Lars V
LV
Uthaman
Smitha B
SB
Hortsch
Michael
M
Murphey
Rodney K
RK
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017124:Conserved Sequence; D004330:Drosophila / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004553:Electric Conductivity; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D020125:Mutation, Missense; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D040681:Structural Homology, Protein; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure
D015816:Cell Adhesion Molecules, Neuronal; D029721:Drosophila Proteins; D039842:Neural Cell Adhesion Molecule L1; C061745:Nrg protein, Drosophila