# ER Morphology in the Pathogenesis of Hereditary
## 3 ER Shaping Proteins  
The ER is a continuous membrane network that extends throughout the cytoplasm of eukaryotic cells. The peripheral ER comprises a network of tubules and sheet-like structures in continuity with the nuclear envelope. Traditionally, ER cisternae have been classified as ribosome bound, \"rough\" ER (RER), while ER tubules are considered ribosome-free, \"smooth\" ER (SER). The purpose of differently shaped ER domains has not been fully established. Cisternae are characterized by a larger luminal volume vs. surface area, compared to tubules, suggesting that they would be the preferred site for processes, such as protein folding, taking place in the ER lumen [23; 24; 25]. Conversely, ER tubules are considered the preferential location for lipid synthesis and membrane protein accumulation [24]. Accordingly, the relative abundance of RER and SER in different cell types often correlates with their function (with secretory cells, for example, containing mainly RER) [26]. Nevertheless, recent evidence suggests that the distinction between ER tubules and cisternae can be blurred. Structural analysis performed on EM sections showed that the transformation of long cisternae into tubules during mitosis in cultured cells occurs via the progressive formation and expansion of fenestrations [25]. Moreover, it has been reported that ER tubules can also be decorated with ribosomes, albeit at lower densities than in cisternae [24; 25]. Thanks to super-resolution imaging technologies, other \"unconventional\" ER structures have been discovered that have traditionally been categorized as cisternae due to the limited spatiotemporal resolution of standard optical microscopy. These comprise clusters of highly dense peripheral tubules [27] as well as sheets fenestrated by \"nanoholes\" [28] and ribosome-associated vesicles [29].  
Owing to its particular shape and function, the neuronal ER needs further tweaks and adjustments to fit in cell bodies, and especially in dendrites or axons. Indeed, neuronal cell bodies contain both SER and RER with highly dynamic transitions between each other [30]. Stacked sheets are connected by helicoidal structures, providing an extended surface for ribosomes [31] to perform protein translation. The axonal ER is primarily tubular, with an enrichment in a population of very narrow tubules (\(\sim\)20-30 nm in diameter) [32]. The RER constitutes a very small fraction of axonal ER [33], suggesting a limited contribution of ER-associated ribosomes to local protein translation. The narrow tubules within axons and dendrites do not connect together in three-way junctions as in cell bodies, probably due to curvature constraints as a result of the small diameter of these neuronal protrusions. Instead, they connect at the edges of sheets with high curvature [32].  
Altogether, these findings support a model for ER network based on a highly dynamic continuum of membrane structures that can undergo rapid interconversion in order to support fast rearrangements of the peripheral ER. Although the purpose of the constant reorganization of the ER network is not completely understood, it is reasonable to speculate that ER dynamics help reconfigure the spatial organization of the network in response to specific intracellular stimuli. A few basic processes contribute to ER dynamics, including fusion and fission, elongation, retraction, and branching of tubules. In recent years, progress has been made in understanding how the architecture of the ER is generated and maintained, thanks in particular to the discovery of ER-shaping proteins that are specifically designed to create and maintain the highly complex structure of the ER [34].