Endoplasmic reticulum morphology regulation by RTN4 modulates neuronal regeneration by curbing luminal transport
Tasuku Konno, Pierre Parutto, Cécile C. Crapart, Valentina Davì, David M. Bailey, Mosab Ali Awadelkareem, Colin Hockings, Aidan I. Brown, Katherine M. Xiang, Anamika Agrawal, Joseph E. Chambers, Molly J. Vander Werp, Katherine Koning, Louis M. Elfari, Sam Steen, Emmanouil Metzakopian, Laura M. Westrate, Elena F. Koslover, Edward Avezov
Abstract
Cell functions rely on intracellular transport systems distributing bioactive molecules with high spatiotemporal accuracy. The endoplasmic reticulum (ER) tubular network constitutes a system for delivering luminal solutes, including Ca 2+ , across the cell periphery. How the ER structure enables this nanofluidic transport system is unclear. Here, we show that ER membrane-localized reticulon 4 (RTN4/Nogo) is sufficient to impose neurite outgrowth inhibition in human cortical neurons while acting as an ER morphoregulator. Improving ER transport visualization methodologies combined with optogenetic Ca 2+ dynamics imaging and in silico modeling, we observed that ER luminal transport is modulated by ER tubule narrowing and dilation, proportional to the amount of RTN4. Excess RTN4 limited ER luminal transport and Ca 2+ release, while RTN4 elimination reversed the effects. The described morphoregulatory effect of RTN4 defines the capacity of the ER for peripheral Ca 2+ delivery for physiological releases and thus may constitute a mechanism for controlling the (re)generation of neurites.