Abstract
During axon guidance, growth cones navigate toward attractive cues by inserting new membrane on the cue side. This process depends on Ca(2+) release from endoplasmic reticulum (ER) Ca(2+) channels, but the Ca(2+) sensor and effector governing this asymmetric vesicle export remain unknown. We identified a protein complex that controls asymmetric ER Ca(2+)-dependent membrane vesicle export. The Ca(2+)-dependent motor protein myosin Va (MyoVa) tethers membrane vesicles to the ER via a common bindingsite on the two major ER Ca(2+) channels, inositol1,4,5-trisphosphate and ryanodine receptors. In response to attractive cues, micromolar Ca(2+) from ER channels triggers MyoVa-channel dissociation and the movement of freed vesicles to the cue side, enabling growth cone turning. MyoVa-Ca(2+) channel interactions are required for proper long-range axon growth in developing spinal cord invivo. These findings reveal a peri-ER membrane export pathway for Ca(2+)-dependent attraction in axon guidance.
Highlights
In neurons, membrane export is tightly regulated by Ca2+ to enable the precise spatial and temporal control of membrane vesicle biogenesis, storage, transport, and exocytosis at target membranes
For neurons that undergo long-distance axon migration guided by external cues, the synaptic vesicle release machinery is not well positioned to process membrane vesicles for fusion, nor does the presynaptic terminal allow control of the direction of vesicle targeting to the plasma membrane, because active zone release sites are non-mobile
Because the turning direction of growth cones after photolysis of caged Ca2+ depends on the occurrence of CICR, Ca2+-elicited attraction can be converted to repulsion by pre-treating growth cones with a high dose of ryanodine that blocks RyR3 in dorsal root ganglion (DRG) neurons (Ooashi et al, 2005)
Summary
Membrane export is tightly regulated by Ca2+ to enable the precise spatial and temporal control of membrane vesicle biogenesis, storage, transport, and exocytosis at target membranes. The canonical Ca2+-dependent synaptic vesicle release mechanism involves the fusion of docked synaptic vesicles with the neuronal plasma membrane after Ca2+ diffusion through voltage-gated Ca2+ channels (Parekh, 2008). In this system, specificity is achieved by the colocalization of a Ca2+ sensor synaptotagmin, the vesicle docking and priming machinery, and Ca2+ channels (Eggermann et al, 2011). For neurons that undergo long-distance axon migration guided by external cues, the synaptic vesicle release machinery is not well positioned to process membrane vesicles for fusion, nor does the presynaptic terminal allow control of the direction of vesicle targeting to the plasma membrane, because active zone release sites are non-mobile. Such guidance cues attract or repel an axon by elevating cytosolic Ca2+ concentrations asymmetrically on the side of the growth cone facing higher concentrations of the cues
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