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. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule - lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule - lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function.
Polarized cargo transport is essential for neuronal function. However, the minimal basic components required for selective cargo sorting and distribution in neurons remain elusive. We found that in ...sensory neurons the axon initial segment is largely absent and that microtubule-associated protein 2 (MAP2) defines the cargo-filtering zone in the proximal axon. Here, MAP2 directs axonal cargo entry by coordinating the activities of molecular motors. We show that distinct kinesins differentially regulate cargo velocity: kinesin-3 drives fast axonal cargo trafficking, while kinesin-1 slows down axonal cargo transport. MAP2 inhibits “slow” kinesin-1 motor activity and allows kinesin-3 to drive robust cargo transport from the soma into the axon. In the distal axon, the inhibitory action of MAP2 decreases, leading to regained kinesin-1 activity and vesicle distribution. We propose that selective axonal cargo trafficking requires the MAP2-defined pre-axonal filtering zone and the ability of cargos to switch between distinct kinesin motor activities.
•MAP2 defines a unique pre-axonal cargo filtering zone in sensory neurons•MAP2 regulates axonal cargo entry by preventing KIF5 binding to microtubules•MAP2 promotes axonal cargo spreading by balancing KIF1 and KIF5 motor activities•MAP2 controls the axonal growth potential of sensory neurons
Gumy et al. demonstrate that MAP2 defines a unique pre-axonal cargo filtering zone in sensory neurons that coordinates the activity of distinct kinesin motor proteins to drive selective cargo sorting and distribution in axons.
Liprins are highly conserved scaffold proteins that regulate cell adhesion, cell migration, and synapse development by binding to diverse target proteins. The molecular basis governing liprin/target ...interactions is poorly understood. The liprin-α2/CASK complex structure solved here reveals that the three SAM domains of liprin-α form an integrated supramodule that binds to the CASK kinase-like domain. As supported by biochemical and cellular studies, the interaction between liprin-α and CASK is unique to vertebrates, implying that the liprin-α/CASK interaction is likely to regulate higher-order brain functions in mammals. Consistently, we demonstrate that three recently identified X-linked mental retardation mutants of CASK are defective in binding to liprin-α. We also solved the liprin-α/liprin-β SAM domain complex structure, which uncovers the mechanism underlying liprin heterodimerizaion. Finally, formation of the CASK/liprin-α/liprin-β ternary complex suggests that liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities.
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► The liprin-α2 SAM repeats/CASK kinase domain complex structure is solved ► A unique insertion between SAM1 and 2 is required for liprin-α2 to bind to CASK ► X-linked mental retardation mutants of CASK are defective in binding to liprin-α ► The liprin-α/β complex structure suggests a suprasignaling complex assembly mode
Compassion is a particular form of empathic reaction to harm that befalls others and is accompanied by a desire to alleviate their suffering. This altruistic behavior is often manifested through ...altruistic punishment, wherein individuals penalize a deprecated human's actions, even if they are directed toward strangers. By adopting a dual approach, we provide empirical evidence that compassion is a multifaceted prosocial behavior and can predict altruistic punishment. In particular, in this multiple-brain connectivity study in an EEG hyperscanning setting, compassion was examined during real-time social interactions in a third-party punishment (TPP) experiment. We observed that specific connectivity patterns were linked to behavioral and psychological intra- and interpersonal factors. Thus, our results suggest that an ecological approach based on simultaneous dual-scanning and multiple-brain connectivity is suitable for analyzing complex social phenomena.
In cultured vertebrate neurons, axons have a uniform arrangement of microtubules with plus-ends distal to the cell body (plus-end-out), whereas dendrites contain mixed polarity orientations with both ...plus-end-out and minus-end-out oriented microtubules. Rather than non-uniform microtubules, uniparallel minus-end-out microtubules are the signature of dendrites in Drosophila and Caenorhabditis elegans neurons. To determine whether mixed microtubule organization is a conserved feature of vertebrate dendrites, we used live-cell imaging to systematically analyze microtubule plus-end orientations in primary cultures of rat hippocampal and cortical neurons, dentate granule cells in mouse organotypic slices, and layer 2/3 pyramidal neurons in the somatosensory cortex of living mice. In vitro and in vivo, all microtubules had a plus-end-out orientation in axons, whereas microtubules in dendrites had mixed orientations. When dendritic microtubules were severed by laser-based microsurgery, we detected equal numbers of plus- and minus-end-out microtubule orientations throughout the dendritic processes. In dendrites, the minus-end-out microtubules were generally more stable and comparable with plus-end-out microtubules in axons. Interestingly, at early stages of neuronal development in nonpolarized cells, newly formed neurites already contained microtubules of opposite polarity, suggesting that the establishment of uniform plus-end-out microtubules occurs during axon formation. We propose a model in which the selective formation of uniform plus-end-out microtubules in the axon is a critical process underlying neuronal polarization.
Live-cell imaging was used to systematically analyze microtubule organization in primary cultures of rat hippocampal neurons, dentate granule cells in mouse organotypic slices, and layer 2/3 pyramidal neuron in somatosensory cortex of living mice. In vitro and in vivo, all microtubules have a plus-end-out orientation in axons, whereas microtubules in dendrites have mixed orientations. Interestingly, newly formed neurites of nonpolarized neurons already contain mixed microtubules, and the specific organization of uniform plus-end-out microtubules only occurs during axon formation. Based on these findings, the authors propose a model in which the selective formation of uniform plus-end-out microtubules in the axon is a critical process underlying neuronal polarization.
Axon and dendritic trafficking Maeder, Celine I; Shen, Kang; Hoogenraad, Casper C
Current opinion in neurobiology,
08/2014, Letnik:
27
Journal Article
Recenzirano
Highlights • Mechanisms of cargo sorting in axons and dendrites. • Mechanisms of cargo motility and anchoring. • Mechanisms of cargo delivery and capturing.
Local microtubule remodeling plays a crucial role in controlling the transport of neuronal cargo. A new study reveals that excitatory en passant boutons in the axon are hotspots for activity-induced ...microtubule nucleation and provide tracks for interbouton vesicle trafficking.
Local microtubule remodeling plays a crucial role in controlling the transport of neuronal cargo. A new study reveals that excitatory en passant boutons in the axon are hotspots for activity-induced microtubule nucleation and provide tracks for interbouton vesicle trafficking.
Post‐translational modifications of tubulin can regulate the dynamics and mechanical properties of microtubules and their interactions with different proteins, such as molecular motors. Two studies ...now demonstrate that excessive accumulation of a specific modification, polyglutamylation, leads to neurodegeneration in mice and humans, likely due to defects in axonal microtubule‐based transport.
While tubulin glutamylation is needed to sustain intracellular transport in neurons, the formation of excessive polyglutamylation results in neurodegenerative phenotypes in mice and human patients.
Cytoplasmic dynein is the major microtubule minus-end-directed cellular motor. Most dynein activities require dynactin, but the mechanisms regulating cargo-dependent dynein-dynactin interaction are ...poorly understood. In this study, we focus on dynein-dynactin recruitment to cargo by the conserved motor adaptor Bicaudal D2 (BICD2). We show that dynein and dynactin depend on each other for BICD2-mediated targeting to cargo and that BICD2 N-terminus (BICD2-N) strongly promotes stable interaction between dynein and dynactin both in vitro and in vivo. Direct visualization of dynein in live cells indicates that by itself the triple BICD2-N-dynein-dynactin complex is unable to interact with either cargo or microtubules. However, tethering of BICD2-N to different membranes promotes their microtubule minus-end-directed motility. We further show that LIS1 is required for dynein-mediated transport induced by membrane tethering of BICD2-N and that LIS1 contributes to dynein accumulation at microtubule plus ends and BICD2-positive cellular structures. Our results demonstrate that dynein recruitment to cargo requires concerted action of multiple dynein cofactors.
Accumulation of abnormal Tau is a characteristic feature of a number of neurodegenerative disorders, called tauopathies. What is the reason for Tau toxicity in neuronal cells? In this issue of ...Neuron, Sohn et al. (2019) found that FTD mutant Tau-V337M blocks axon initial segment (AIS) plasticity, causing neuronal hyperexcitability.
Accumulation of abnormal Tau is a characteristic feature of a number of neurodegenerative disorders, called tauopathies. What is the reason for Tau toxicity in neuronal cells? In this issue of Neuron, Sohn et al. (2019) found that FTD mutant Tau-V337M blocks axon initial segment (AIS) plasticity, causing neuronal hyperexcitability.
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