Trends in Cell Biology
ReviewThe endoplasmic reticulum and protein trafficking in dendrites and axons
Introduction
Polarized protein trafficking is a crucial determinant of neuronal morphogenesis and synaptic function which in turn govern connectivity and information processing. The marked cellular asymmetry that is established during neuronal differentiation is maintained throughout the lifespan of an organism. At the level of the individual neurons, this asymmetry begins with one neurite growing at a faster rate. This neurite generates the axon, whereas the remaining neurites develop into a complex and diverse dendritic arbor [1]. The establishment and maintenance of neuronal polarity is critically dependent on the integrity and spatial organization of the secretory pathway [2]. For example, altering the orientation of the Golgi apparatus in hippocampal neurons, which is constituted by a perinuclear organelle oriented towards the apical dendrite and additional satellite structures distributed throughout the dendritic arbor (Golgi outposts), differentially limits dendritic growth [3].
Synapses are specialized and dynamic structures formed at the junction of two communicating neurons. Intracellular trafficking of synaptic proteins and neurotransmitter receptors plays a key role in synapse formation and in the regulation of synaptic strength [4]. For instance, rapid insertion or removal of AMPA-type glutamate receptors (AMPARs) modifies synaptic strength during experience-dependent plasticity, providing a molecular correlate for cognitive functions [5].
The endomembrane trafficking system in eukaryotic cells includes a forward biosynthetic route constituted by the ER, the ER–Golgi intermediate compartment (ERGIC, Glossary), the Golgi apparatus and post-Golgi vesicles, and a recycling-degradative route constituted by endosomes and lysosomes. In neurons, little is known of how the membrane trafficking mechanisms found in simpler cells have adapted spatially to accommodate the unparalleled morphological requirements of the neuron. Recent studies have begun to elucidate the function of satellite Golgi outposts and endosomes in polarized neuronal trafficking 4, 6, 7, 8, 9. By contrast, the dynamic structure of the ER in dendrites and axons remains for the most part unexplored 10, 11. Importantly, the relevance of axo-dendritic ER trafficking and its contribution to neuronal morphogenesis and synaptic function are still major unanswered questions.
In this review we examine the structural and dynamic features of the neuronal ER and consider its function in the control of local axo-dendritic trafficking and the assembly and export of neurotransmitter receptors. We also discuss the contribution of the ER to synaptic plasticity and pathology.
Section snippets
The structure of the ER in dendrites and axons
The ER is a single and continuous membrane-bound organelle responsible for lipid and sterol synthesis, the synthesis and post-translational modification of most secretory and membrane proteins, and the regulation of Ca2+ levels and arachidonic acid release. The shape of the ER is heterogeneous, and varies between cell types and cell stages, but can be divided into three domains: the nuclear envelope, the ribosome-bound rough ER (RER) and the ribosome-free smooth ER (SER) [12]. Structurally the
ER dynamics in neurons
The ER network is constantly remodeling (reviewed in 13, 45) and three major components contribute to its mobility. First, mobility is achieved by rapid ER tubule extension along microtubules, also referred to as microtubule sliding. In VERO cells, a kidney epithelial cell lineage, tubules extend toward the cell periphery driven by kinesin-1, and towards the cell center powered by cytoplasmic dynein [46]. The adaptor protein kinectin probably mediates kinesin-1 binding to ER membranes [20]. ER
Protein trafficking within the neuronal ER
Major issues presently under study include the role of local secretory organelles in the rapid entry and exit of neurotransmitter receptors from synaptic sites, and the contribution of ER dynamics to this process. Current evidence indicates that there are two protein-trafficking modalities in dendrites (Figure 2). In the canonical secretory route, membrane proteins are synthesized and exported from the somatic ER to a centralized Golgi compartment. Proteins are then sorted by means of
Trafficking signals for ER retention and export
ER retention and export control the assembly and plasma-membrane delivery of multi-subunit neurotransmitter receptors and ion channels. They prevent unassembled or misfolded proteins from reaching the plasma membrane, thereby avoiding deleterious effects on neuronal function and survival. It has been firmly established that sequences different from KDEL and di-lysine, the best-described ER retrieval/recycling and retention signals for ER luminal and membrane proteins, control the trafficking of
Protein trafficking to post-ER compartments
Post-ER secretory compartments located distally support a functional role for dendritic and axonal ER trafficking. Cargo exits the ER to enter the ERGIC in dendrites [9], and specific markers for ERGIC (Rab1 and ERGIC-53) and Golgi (Giantin) have been reported in distal dendrites and dendritic spines 6, 28, 57. A trihydrophobic motif (VMI 569–571) of the GABA transporter 1 (GAT1) is required for export from the ERGIC, and substitution of these residues results in accumulation of GAT1 in
The role of the ER in synaptic plasticity and pathology
The close proximity of the ER to inhibitory postsynaptic sites and the presence of the spine apparatus in a subset of excitatory dendritic spines implicate the ER in the modulation of synaptic transmission [25]. Interestingly, ER export of NMDARs near synaptic sites is regulated by neuronal activity, supporting this hypothesis [31]. In addition, a subset of spines in hippocampal CA1 pyramidal cells contain ER structures that are continuous with the dendritic ER [104]. These spines have
Concluding remarks
The actively shaped ER network supports high connectivity and segregated functions, but central questions concerning the structure, dynamics and function of the ER in dendrites and axons remain open. Increased understanding of the ER in non-neuronal cells will certainly provide a basis for structural and dynamic analyses in neurons. Pioneering studies have already demonstrated that reticulon proteins RTN2B and RTN3 are localized to developing neurites, and that overexpression of RTN3 causes
Acknowledgments
A.C. is funded by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 1100137, O.A.R. is funded by FONDECYT grant 3110157, and A.C. and O.A.R. are funded by Iniciativa Científica Milenio (ICM) grant P07-048-F.
Glossary
- COPII
- coat protein complex II, required for the formation of ER-to-Golgi transport vesicles.
- dERES
- ER exit sites in dendrites.
- ERES
- ER exit sites.
- ER fragmentation
- loss of ER continuity in response to signaling cascades, yet to be fully characterized.
- ERGIC
- ER–Golgi apparatus intermediate compartment.
- Golgi outposts
- dendritic satellite organelles equivalent to the Golgi apparatus.
- Rapid tubule extension
- the formation of ER tubules along microtubules driven by molecular motors, also referred to as ER sliding.
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