Axonal endoplasmic reticulum tubules control local translation via P180/RRBP1-mediated ribosome interactions.

Local mRNA translation in axons is critical for the spatiotemporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons; however, how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing rat hippocampal cultured neurons.

Endoplasmic reticulum - condensate interactions in protein synthesis and secretion.

In the past decade, a growing amount of evidence has demonstrated that organelles do not act autonomously and independently but rather communicate with each other to coordinate different processes for proper cellular function. With a highly extended network throughout the cell, the endoplasmic reticulum (ER) plays a central role in interorganelle communication through membrane contact sites. Here, we highlight recent evidence indicating that the ER also forms contacts with membrane-less organelles.

A voyage from the ER: spatiotemporal insights into polarized protein secretion in neurons.

To function properly, neurons must maintain a proteome that differs in their somatodendritic and axonal domain. This requires the polarized sorting of newly synthesized secretory and transmembrane proteins into different vesicle populations as they traverse the secretory pathway. Although the trans-Golgi-network is generally considered to be the main sorting hub, this sorting process may already begin at the ER and continue through the Golgi cisternae.

Stress-induced phase separation of ERES components into Sec bodies precedes ER exit inhibition in mammalian cells.

Phase separation of components of ER exit sites (ERES) into membraneless compartments, the Sec bodies, occurs in Drosophila cells upon exposure to specific cellular stressors, namely, salt stress and amino acid starvation, and their formation is linked to the early secretory pathway inhibition. Here, we show Sec bodies also form in secretory mammalian cells upon the same stress. These reversible and membraneless structures are positive for ERES components, including both Sec16A and Sec16B isoforms and COPII subunits.

Moving the ER tip by tip.

Endoplasmic reticulum (ER) and microtubule (MT) interactions have been observed in different cell types. However, how these interactions are regulated remains unknown. In this issue of Developmental Cell, Nourbakhsh et al.

ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability.

Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons.

Organelle distribution in neurons: Logistics behind polarized transport.

Highly polarized neurons need to carefully regulate the distribution of organelles and other cargoes into their two morphologically and functionally distinct domains, the somatodendritic and axonal compartments, to maintain proper neuron homeostasis. An outstanding question in the field is how organelles reach their correct destination. Long-range transport along microtubules, driven by motors, ensures a fast and controlled availability of organelles in axons and dendrites, but it remains largely unclear what rules govern their transport into the correct compartment.

Complex Interactions Between Membrane-Bound Organelles, Biomolecular Condensates and the Cytoskeleton.

Membrane-bound and membraneless organelles/biomolecular condensates ensure compartmentalization into functionally distinct units enabling proper organization of cellular processes. Membrane-bound organelles form dynamic contacts with each other to enable the exchange of molecules and to regulate organelle division and positioning in coordination with the cytoskeleton. Crosstalk between the cytoskeleton and dynamic membrane-bound organelles has more recently also been found to regulate cytoskeletal organization.

Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity.

Establishment of neuronal polarity depends on local microtubule (MT) reorganization. The endoplasmic reticulum (ER) consists of cisternae and tubules and, like MTs, forms an extensive network throughout the entire cell. How the two networks interact and control neuronal development is an outstanding question.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon.

The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood.

BORC Functions Upstream of Kinesins 1 and 3 to Coordinate Regional Movement of Lysosomes along Different Microtubule Tracks.

The multiple functions of lysosomes are critically dependent on their ability to undergo bidirectional movement along microtubules between the center and the periphery of the cell. Centrifugal and centripetal movement of lysosomes is mediated by kinesin and dynein motors, respectively. We recently described a multi-subunit complex named BORC that recruits the small GTPase Arl8 to lysosomes to promote their kinesin-dependent movement toward the cell periphery.

Imaging the Polarized Sorting of Proteins from the Golgi Complex in Live Neurons.

The study of polarized protein trafficking in live neurons is critical for understanding neuronal structure and function. Given the complex anatomy of neurons and the numerous trafficking pathways that are active in them, however, visualization of specific vesicle populations leaving the Golgi complex presents unique challenges. Indeed, several approaches used in non-polarized cells, and even in polarized epithelial cells, have been less successful in neurons.

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon.

An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon.

Mechanisms of Polarized Organelle Distribution in Neurons.

Neurons are highly polarized cells exhibiting axonal and somatodendritic domains with distinct complements of cytoplasmic organelles. Although some organelles are widely distributed throughout the neuronal cytoplasm, others are segregated to either the axonal or somatodendritic domains. Recent findings show that organelle segregation is largely established at a pre-axonal exclusion zone (PAEZ) within the axon hillock.

Sorting of Dendritic and Axonal Vesicles at the Pre-axonal Exclusion Zone.

Polarized sorting of newly synthesized proteins to the somatodendritic and axonal domains of neurons occurs by selective incorporation into distinct populations of vesicular transport carriers. An unresolved issue is how the vesicles themselves are sorted to their corresponding neuronal domains. Previous studies concluded that the axon initial segment (AIS) is an actin-based filter that selectively prevents passage of somatodendritic vesicles into the axon.

Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1.

Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu(2+) transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the σ1 subunit of the clathrin adaptor AP-1. Under basal Cu(2+) conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon.

Co-assembly of viral envelope glycoproteins regulates their polarized sorting in neurons.

Newly synthesized envelope glycoproteins of neuroinvasive viruses can be sorted in a polarized manner to the somatodendritic and/or axonal domains of neurons. Although critical for transneuronal spread of viruses, the molecular determinants and interregulation of this process are largely unknown. We studied the polarized sorting of the attachment (NiV-G) and fusion (NiV-F) glycoproteins of Nipah virus (NiV), a paramyxovirus that causes fatal human encephalitis, in rat hippocampal neurons.

Going forward with retromer.

The retromer complex is well known to mediate retrograde transport from endosomes to the Golgi. In a recent issue of Neuron, Choy et al. (2014) identify a function for retromer in supporting fast, local delivery of neurotransmitter receptors from endosomes to the dendritic plasma membrane.

Nicotine prevents synaptic impairment induced by amyloid-β oligomers through α7-nicotinic acetylcholine receptor activation.

An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-β (Aβ) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the α7-nicotinic acetylcholine receptor (α7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective α7-nAChR agonist, protects from morphological and synaptic impairments induced by Aβ oligomers.

Signal-mediated, AP-1/clathrin-dependent sorting of transmembrane receptors to the somatodendritic domain of hippocampal neurons.

Plasma membranes of the somatodendritic and axonal domains of neurons are known to have different protein compositions, but the molecular mechanisms that determine this polarized protein distribution remain poorly understood. Herein we show that somatodendritic sorting of various transmembrane receptors in rat hippocampal neurons is mediated by recognition of signals within the cytosolic domains of the proteins by the μ1A subunit of the adaptor protein-1 (AP-1) complex. This complex, in conjunction with clathrin, functions in the neuronal soma to exclude somatodendritic proteins from axonal transport carriers.

Adaptor protein 2-mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing.

The β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins.

Wnt-5a is a synaptogenic factor with neuroprotective properties against Aβ toxicity.

Background: We have recently found that Wnt-5a regulates the synaptic structure and function in hippocampal neurons. This ligand is expressed in the hippocampus, stimulates dendritic spine morphogenesis and increases glutamatergic neurotransmission. Moreover, we have also shown that Wnt-5a induces the clustering of PSD-95.

Wnt-5a modulates recycling of functional GABAA receptors on hippocampal neurons.

GABA(A) receptors (GABA(A)-Rs) play a significant role in mediating fast synaptic inhibition and it is the main inhibitory receptor in the CNS. The role of Wnt signaling in coordinating synapse structure and function in the mature CNS is poorly understood. In previous studies we found that Wnt ligands can modulate excitatory synapses through remodeling both presynaptic and postsynaptic regions.

Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Background: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.