Model of effect of Rtnl1 loss on presynaptic ER network and synaptic function. Schematic diagrams of a WT and a Rtnl1 mutant (Rtnl1⁻) presynaptic terminal. The latter shows fewer ER tubules, resulting in less ER network surface, and hence in less ER contact surface with other cell compartments. Reduced presynaptic ER surface is accompanied by generally lower Ca²⁺ fluxes in presynaptic compartments (cytosol, ER lumen, and mitochondria), and by lower neurotransmission. These reductions could be a potential route by which the loss of ER-shaping HSP protein function might lead to motor neuron axonopathy. Key: ER network, blue; mitochondria, purple; synaptic vesicles, gray; MN PM, dark orange; muscle PM, dark red; ER-PM contacts, accumulation of STIM1 (red rods); released neurotransmitter, black dots.