Abstract
Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases.
Highlights
Pre-synaptic components, such as precursors of synaptic vesicles, active zone compartments, mitochondria and proteins essential for synaptic vesicle release must be transported down the axon to the nerve terminals by the anterograde motor kinesin-1 [1,2,3,4]
Receptor activation leads to an increase in the phosphorylation of R-Smad, Mad at the neuromuscular junction (NMJ) terminals followed by nuclear translocation of phospho Mad (p-Mad) in the brain through its interaction with the co-Smad, Medea [9]
We have identified that perturbations in axonal transport disrupts the bone morphogenetic protein (BMP) signaling pathway, a pathway essential for synaptic formation, maintenance and function of the Drosophila NMJ
Summary
Pre-synaptic components, such as precursors of synaptic vesicles, active zone compartments, mitochondria and proteins essential for synaptic vesicle release must be transported down the axon to the nerve terminals by the anterograde motor kinesin-1 [1,2,3,4]. A mutation of the dynein–dynactin motor p150/glued disrupted retrograde axonal transport of activated BMP as assayed by the loss of its downstream signal phospho Mad (p-Mad) accumulation in motor neuron nuclei [10], indicating that perhaps this signal could be incorporated into a signaling endosome that is transported by dynein motors [9], similar to the signaling endosome NGF-TrkA in neurotrophin signaling [11]. Whether such a BMP signaling endosome exists and whether this complex is transported via a direct interaction with molecular motors is unclear. Since the BMP ligands and receptors are expressed in multiple cells in the CNS [10,11,12,13] how BMP signaling at the CNS plays a role in normal NMJ development and function at the distal ends of neurons is unknown
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