Endoplasmic Reticulum morphological regulation by RTN4/NOGO modulates neuronal regeneration by slowing luminal transport

Cell and tissue functions rely on an elaborate intracellular transport system responsible for distributing bioactive molecules with high spatiotemporal accuracy. The tubular network of the Endoplasmic Reticulum (ER) constitutes a system for the delivery of luminal solutes it stores, including Ca2+, across the cell periphery. The physical nature and factors underlying the ERs functioning as a fluidics system are unclear. Using an improved ER transport visualisation methodology combined with optogenetic Ca2+ dynamics imaging, we observed that ER luminal transport is modulated by natural ER tubule narrowing and dilation, directly proportional to the amount of an ER membrane morphogen, Reticulon 4 (RTN4). Consequently, the ER morphoregulatory effect of RTN4 defines ERs capacity for peripheral Ca2+ delivery and thus controls axonogenesis. Excess RTN4 limited ER luminal transport, Ca2+ release and iPSC-derived cortical neurons axonal extension, while RTN4 elimination reversed the effects. SummaryIntracellular transport through the lumen of the ER network is modulated through narrowing/dilation of ER tubules by a membrane morphogen - RTN4, a process controlling axonogenesis by limiting the delivery of ER-stored Ca2+.