Endoplasmic reticulum morphology regulation by RTN4 modulates neuronal regeneration by curbing luminal transport

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114357
• Main Authors: Konno, Tasuku, Parutto, Pierre, Crapart, Cécile C., Davì, Valentina, Bailey, David M.D., Awadelkareem, Mosab Ali, Hockings, Colin, Brown, Aidan I., Xiang, Katherine M., Agrawal, Anamika, Chambers, Joseph E., Vander Werp, Molly J., Koning, Katherine M., Elfari, Louis Mounir, Steen, Sam, Metzakopian, Emmanouil, Westrate, Laura M., Koslover, Elena F., Avezov, Edward
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2024
• Subjects: CP: Cell biology; CP: Neuroscience
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114357

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 Ca2+, 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 Ca2+ 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 Ca2+ release, while RTN4 elimination reversed the effects. The described morphoregulatory effect of RTN4 defines the capacity of the ER for peripheral Ca2+ delivery for physiological releases and thus may constitute a mechanism for controlling the (re)generation of neurites. [Display omitted] •Neurite outgrowth inhibition effect of RTN4 originates from the ER•Dose of RTN4 modulates the width of ER tubules•RTN4 curbs local ER calcium release by hindering luminal transport Konno et al. report that reticulon 4 (RTN4), an endoplasmic reticulum (ER) morphogen also known as neurite outgrowth inhibitor (Nogo), negatively regulates the transport of ER luminal materials such as calcium by modulating the size of ER tubules, defining a direct link of ER morphoregulation to neuronal activity.