JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation

Watt, Dana; Dixit, Ram; Cavalli, Valeria

doi:10.1074/jbc.m115.651885

Cited by 35 publications

(59 citation statements)

References 78 publications

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“…Indeed, there is genetic evidence in mice that JIP3 can function as an adaptor that promotes the Kinesin-1-mediated transport of TrkB receptors as well as one or more unidentified cargos relevant to axon elongation and neuronal degeneration (Huang et al 2011;Sun et al 2013;Sato et al 2015;Watt et al 2015).…”

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confidence: 99%

UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons

Edwards¹,

Morrison²,

Yorks³

et al. 2015

Genetics

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The conserved protein UNC-16 (JIP3) inhibits the active transport of some cell soma organelles, such as lysosomes, early endosomes, and Golgi, to the synaptic region of axons. However, little is known about UNC-16's organelle transport regulatory function, which is distinct from its Kinesin-1 adaptor function. We used an unc-16 suppressor screen in Caenorhabditis elegans to discover that UNC-16 acts through CDK-5 (Cdk5) and two conserved synapse assembly proteins: SAD-1 (SAD-A Kinase), and SYD-2 (Liprin-a). Genetic analysis of all combinations of double and triple mutants in unc-16(+) and unc-16(2) backgrounds showed that the three proteins (CDK-5, SAD-1, and SYD-2) are all part of the same organelle transport regulatory system, which we named the CSS system based on its founder proteins. Further genetic analysis revealed roles for SYD-1 (another synapse assembly protein) and STRADa (a SAD-1-interacting protein) in the CSS system. In an unc-16(2) background, loss of the CSS system improved the sluggish locomotion of unc-16 mutants, inhibited axonal lysosome accumulation, and led to the dynein-dependent accumulation of lysosomes in dendrites. Time-lapse imaging of lysosomes in CSS system mutants in unc-16(+) and unc-16(2) backgrounds revealed active transport defects consistent with the steady-state distributions of lysosomes. UNC-16 also uses the CSS system to regulate the distribution of early endosomes in neurons and, to a lesser extent, Golgi. The data reveal a new and unprecedented role for synapse assembly proteins, acting as part of the newly defined CSS system, in mediating UNC-16's organelle transport regulatory function.KEYWORDS Caenorhabditis elegans; axonal transport; JIP3; Cdk5; Liprin; SAD-A; dynein N EURONS have a unique architecture consisting of a cell soma, one or more dendrites that receive information, and a single axon, which can be a single process or intricately branched. Part of the axon is specialized to form synapses, which integrate and transmit information to other neurons or muscle cells via synaptic vesicles and dense core vesicles. This unique architecture and cell biology places extraordinary demands on the membrane-trafficking and transport machinery. In addition to transporting synaptic vesicles and dense core vesicles long distances into axons, motor neurons must also restrict, or even prevent, the flow of some organelles, including Golgi, lysosomes, and endosomes, into the synaptic region of their axons, which, under normal conditions, are relatively devoid of these organelles compared to cell somas. However, there may be special conditions, such as the need for axon repair or growth, where neurons require cell soma organelles in their axons, so the regulatory system for organelle transport must include components that inhibit, as well as promote, axonal transport. The association of mutations in the axonal transport machinery with neurodegenerative disorders in mice and humans underscores the importance of a properly functioning transport system for the long-term viab...

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confidence: 99%

UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons

Edwards¹,

Morrison²,

Yorks³

et al. 2015

Genetics

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“…This study found that a JIP3 mutant that is unable to bind the motor subunit of kinesin-1 (KHC) (42) leads to slow moving kinesin-1 tetramer. When expressed in cultured hippocampal neurons this JIP3 mutant reduces axon growth despite being properly localized to axon tips (71). This study illustrates that in addition to JIP3-dependent localization at axon tips to mediate axon growth (72), JIP3 controls axon growth via a motor processivity-based mechanism.…”

Section: Figmentioning

confidence: 89%

“…Beyond its role in delivering cargo to and from the axon terminal, axonal transport is emerging as a more sophisticated system to regulate signaling. A recent study revealed that regulation of kinesin-1 motility by JIP3 is critical for axon growth and regeneration (71). This study found that a JIP3 mutant that is unable to bind the motor subunit of kinesin-1 (KHC) (42) leads to slow moving kinesin-1 tetramer.…”

Section: Figmentioning

confidence: 94%

“…In this model, reducing the levels of either kinesin or dynein increases axon length (73) but if the amount of signal in the system is conserved, changing motor velocities might also affect axon length. It is important to bear in mind that motors might affect axon elongation in different manners (71,74). For example, BICD-related protein 1 (BICDR-1) accelerates minus-end-directed vesicle movements, reducing the amount of Rab6 vesicle at neurite tip and reducing axon length in both dorsal root ganglia (DRG) and hippocampal neurons.…”

Section: Figmentioning

confidence: 99%

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Signaling Over Distances

Saito

Cavalli

2016

Molecular & Cellular Proteomics

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Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths imply that neurons have mastered efficient mechanisms for long distance signaling between soma and synaptic terminal. These elaborate mechanisms are required for neuronal development and maintenance of the nervous system. Neurons can fine-tune long distance signaling through calcium wave propagation and bidirectional transport of proteins, vesicles, and mRNAs along microtubules. The signal transmission over extreme lengths also ensures that information about axon injury is communicated to the soma and allows for repair mechanisms to be engaged. This review focuses on the different mechanisms employed by neurons to signal over long axonal distances and how signals are interpreted in the soma, with an emphasis on proteomic studies. We also discuss how proteomic approaches could help further deciphering the signaling mechanisms operating over long distance in axons. Neurons have unique and highly polarized morphologies. The axon allows intracellular communication between the cell soma and the distantly located synaptic terminal. The extreme length of axons relative to the cell soma diameter poses great challenges for neuronal development, maintenance, and repair. Anterograde and retrograde axonal transport of proteins vesicles and RNA along the microtubule tracks in the axon is crucial to sustain the required signaling events underlying development and maintenance of the nervous system. The retrograde transport system is also used following axon injury to communicate information from the site of injury back to the soma. Communication between distant axon locations and the cell soma is also ensured by a more rapid signal encoded in calcium waves. Incoming signals from distant axon locations are interpreted by the soma to regulate gene expression for survival or repair. The neuronal epigenome is also influenced by incoming signals to appropriately coordinate transcriptional responses. In this review, we discuss the state of the field regarding the different mechanisms employed by neurons to signal intracellularly over long distances in axons and how signals are interpreted in the cell soma, with an emphasis on proteomic studies. We also discuss how the use of proteomics could further help in understanding long distance signaling system in axons. The communication employed by neurons to signal along dendrites has been reviewed in detail elsewhere (1) and will not be discussed here.Calcium Influx, Back Propagation, and Long Distance Effects-Alterations in axonal calcium levels affect multiple and diverse signaling events, including local protein synthesis and degradation. These local signals can have long distance effects. Axon injury provides a powerful system to study the role of calcium in axonal signaling, because injury-induced calcium influx in the axon triggers important downstream events at the injury site and the soma (Fig.

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“…Мөн JSAP уургууд нь эсийн дотор карго зөөвөрлөдөг мотор уураг болох кинезин-1 -тэй (kinesin-1) харилцан үйлчилж улмаар каргог мотор уурагтай холбодог болохыг судлаачид тогтоожээ [13][14][15][16]. Сүн нар [17] болон Ватт нар [18] JSAP нь мотор уургийн идэвх ба хөдөлгөөнийг зохицуулдаг болохыг харуулсан [13][14][15][16][17][18]. Мэдрэлийн эсийн аксоны уртсах, салаалах, мэдрэлийн ширхэг үүсэхэд ч JSAP уургууд чухал үүрэгтэй ажээ [19][20][21][22].…”

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