Figure 6. APP/DR6 signaling: in vivo evidence, and model.

(a) In control (DR6+/−) P0 diaphragm muscle, few axons (green, neurofilament and synaptophysin stain) overshoot endplates (red, fluorescent alpha-bungarotoxin stain), and those that do are short, but in DR6 mutants more overshoot and many are long (arrowheads), (a′) Number overshooting by > 50 μm (this underestimates the effect, since overshooting axons are longer in mutants). Scale bar: 60 μm (left panels), 15 μm (right).

(b) The “APP/Death Receptor” mechanism. Trophic deprivation triggers cleavage of surface APP by BACE1, releasing sAPPβ, which is further cleaved by an unknown mechanism (“?”) to release N-APP, which binds DR6 to trigger degeneration through caspase-6 in axons and caspase-3 in cell bodies. Also illustrated is cleavage by gamma secretase to release Abeta and the APP intracellular domain (AICD).