Restraint of the Wallenda/DLK MAP Kinase cascade by the Kinesin-3 motor regulates the assembly of synapses

[摘要] Synaptic connections are fundamental units of neuronal communication in the brain. They are composed of precisely opposed pre- and postsynaptic specializations, and these structures are dynamically regulated to adapt to changing needs of neuronal circuits. While mechanisms that regulate the postsynaptic composition of synapses are highly studied, less is known about presynaptic regulation. Within presynaptic terminals, synapse assembly requires the formation of active zones (AZs) and synaptic vesicle (SV) release machinery at synapses. An important role in presynaptic assembly has been assigned to a kinesin-3 family member, Unc-104/Imac/KIF1A. Unc-104/Imac/KIF1A is required for the delivery of synaptic components and SVs to nascent synapses. However, its distinct synaptic phenotype from other kinesins and the complexity of the phenotype is not well understood.This thesis work describes how the synaptic defects of Drosophila unc-104 mutants can be rescued by inhibiting the Wallenda (Wnd)/DLK MAP kinase signaling pathway. This pathway has been previously identified as a regulator of axonal damage signaling and presynaptic terminal morphology. The accessible genetic tools in Drosophila (reviewed in Chapter II) allow for characterization of the mechanistic relationship between Wnd/DLK and Unc-104. Wnd/DLK signaling becomes activated in unc-104 mutants, and inhibits synapse formation independently of Unc-104’s transport functions by controlling the levels and timing of the expression of AZ and SV components (Chapter III). In order to understand the activation mechanism of Wnd signaling, multiple possibilities have been examined (Chapter IV). Cumulative findings lead to a model that accumulated presynaptic proteins in the cell body of unc-104 mutants triggers the Wnd signaling pathway, which then down-regulates presynaptic protein levels. In this fashion Wnd signaling may function as a stress response pathway that regulates the expression level of synaptic proteins according to their ability to be transported in axons. This model also raises an interesting possibility that DLK activation may contribute to synapse malfunction and loss in the aged or diseased nervous system.

[发布机构] University of Michigan

[效力级别] synapse

[关键词] kinesin-3;synapse;Wnd/DLK;presynaptic protein;axonal transport;development and maintenance;Molecular;Cellular and Developmental Biology;Science;Molecular, Cellular, and Developmental Biology