The ER ladder is a unique morphological feature of developing mammalian axons

• Published in: Developmental cell Vol. 57; no. 11; pp. 1369 - 1382.e6
• Main Authors: Zamponi, Emiliano, Meehl, Janet B., Voeltz, Gia K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2022
• Subjects: axon development; cryo-ET; endoplasmic reticulum; microtubule bundle; neurodegeneration; organelle dynamics; organelle shape; organelle dynamics; organelle shape; axon development; neurodegeneration; cryo-ET; microtubule bundle; endoplasmic reticulum
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.05.002

The endoplasmic reticulum (ER) confronts a challenge to accommodate long, smooth ER tubules into the structural complexity of the axonal compartment. Here, we describe a morphological feature for the axonal ER network in developing neurons we termed the ER ladder. Axonal ER ladders are composed of rungs that wrap tightly around the microtubule bundle and dynamic rails, which slide across microtubules. We found that the ER-shaping protein Reticulon 2 determines the architecture and dynamics of the axonal ER ladder by modulating its interaction with microtubules. Moreover, we show that ER ladder depletion impairs the trafficking of associated vesicular axonal cargoes. Finally, we demonstrate that stromal interaction molecule 1 (Stim1) localizes to ER rungs and translocates to ER-plasma membrane contact sites upon depletion of luminal Ca2+. Our findings uncover fundamental insights into the structural and functional organization of the axonal ER network in developing mammalian neurons. [Display omitted] •The ER ladder, composed of ER rails and rungs, is a unique feature of developing axons•ER rails slide along the axon, and rungs cross perpendicularly and tightly around MTs•Reticulon 2 modulates ER ladder structure, ER dynamics, and axonal extension•Stim1 localizes to ER rungs and translocates to ER-PM MCS upon luminal Ca2+ depletion Zamponi et al. utilize high-resolution live fluorescence microscopy and cryo-ET to describe the axonal ER ladder, a morphological feature of developing mammalian neurons. ER ladders contain tubular rails that run the length of the axon and rungs where ER tubules intercalate with regular periodicity around the microtubule bundle.