Abstract
Retrograde signaling is essential for neuronal growth, function and survival; however, we know little about how signaling endosomes might be directed from synaptic terminals onto retrograde axonal pathways. We have identified Khc-73, a plus-end directed microtubule motor protein, as a regulator of sorting of endosomes in Drosophila larval motor neurons. The number of synaptic boutons and the amount of neurotransmitter release at the Khc-73 mutant larval neuromuscular junction (NMJ) are normal, but we find a significant decrease in the number of presynaptic release sites. This defect in Khc-73 mutant larvae can be genetically enhanced by a partial genetic loss of Bone Morphogenic Protein (BMP) signaling or suppressed by activation of BMP signaling in motoneurons. Consistently, activation of BMP signaling that normally enhances the accumulation of phosphorylated form of BMP transcription factor Mad in the nuclei, can be suppressed by genetic removal of Khc-73. Using a number of assays including live imaging in larval motor neurons, we show that loss of Khc-73 curbs the ability of retrograde-bound endosomes to leave the synaptic area and join the retrograde axonal pathway. Our findings identify Khc-73 as a regulator of endosomal traffic at the synapse and modulator of retrograde BMP signaling in motoneurons.
Highlights
Bidirectional communication between the neuronal cell body and distant synaptic terminals is essential for synapse formation, plasticity and neuronal survival [1, 2]
At the Drosophila neuromuscular junction, receptors for the Bone Morphogenic Protein signaling pathway are transported from the synapse to the neuron cell body for the proper establishment of synaptic growth and function of motoneurons
We tested transcriptional activity of Khc-73 by generating a Khc-73-Gal4 fly. Crossing this fly to UAS-mCD8-GFP transgene led to the expression of GFP in most neurons including motor neurons, suggesting that Khc-73 transcription is active in all motor neurons in third instar larvae (S1F and S1G Fig)
Summary
Bidirectional communication between the neuronal cell body and distant synaptic terminals is essential for synapse formation, plasticity and neuronal survival [1, 2]. This is achieved primarily through highly regulated axonal transport. Anterograde transport is mediated by plus-end directed kinesin motor proteins that deliver synaptic vesicles and newly synthesized proteins to the synapse, while retrograde transport of cargo destined for the cell body, such as activated receptor complexes, is accomplished by dynein protein complexes [1, 3,4,5]. Kinesin and dynein motors are required for endosomal traffic within the cell. How activated receptors are preferentially sorted to travel to the nucleus is currently unknown
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