Mutations in<i>Caenorhabditis elegans</i>Cytoplasmic Dynein Components Reveal Specificity of Neuronal Retrograde Cargo

Koushika, Sandhya P.; Schaefer, Anneliese M.; Vincent, Rose; Willis, John H.; Bowerman, Bruce; Nonet, Michael L.

doi:10.1523/jneurosci.5039-03.2004

Cited by 100 publications

(131 citation statements)

References 67 publications

(102 reference statements)

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“…For example, either EHNA or vanadate, which both inhibit dynein and other enzymes, inhibits axonal transport (Ekstrom and Kanje, 1984;Wang et al, 1995;Lalli et al, 2003). More specific dynein inhibition by genetic mutation causes changes in axonal organelle distributions consistent with transport defects (Bowman et al, 1999;Martin et al, 1999a;Koushika et al, 2004). The live analysis here shows that dynein mutations inhibit specific retrograde run parameters and flux but that they leave anterograde transport largely unchanged.…”

Section: Motors For Axonal Transport Of Mitochondriamentioning

confidence: 66%

Kinesin-1 and Dynein Are the Primary Motors for Fast Transport of Mitochondria inDrosophilaMotor Axons

Pilling

Horiuchi

Lively

et al. 2006

MBoC

615

621

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To address questions about mechanisms of filament-based organelle transport, a system was developed to image and track mitochondria in an intact Drosophila nervous system. Mutant analyses suggest that the primary motors for mitochondrial movement in larval motor axons are kinesin-1 (anterograde) and cytoplasmic dynein (retrograde), and interestingly that kinesin-1 is critical for retrograde transport by dynein. During transport, there was little evidence that force production by the two opposing motors was competitive, suggesting a mechanism for alternate coordination. Tests of the possible coordination factor P150 Glued suggested that it indeed influenced both motors on axonal mitochondria, but there was no evidence that its function was critical for the motor coordination mechanism. Observation of organelle-filled axonal swellings ("organelle jams" or "clogs") caused by kinesin and dynein mutations showed that mitochondria could move vigorously within and pass through them, indicating that they were not the simple steric transport blockades suggested previously. We speculate that axonal swellings may instead reflect sites of autophagocytosis of senescent mitochondria that are stranded in axons by retrograde transport failure; a protective process aimed at suppressing cell death signals and neurodegeneration. INTRODUCTIONOrganelle transport is central to the organization, developmental fate, and functions of asymmetric cells. A bipolar neuron is an extreme case, with the somato-dendritic region and the axon containing different sets of proteins and organelles. In general, much of the machinery for synthesizing and recycling neuronal components is clustered near the nucleus. Because an axon, often with an axial ratio of many thousands, usually contains Ͼ99% of the neuronal cytoplasm, active transport of new components away from the cell body and of spent components and trophic materials back toward the cell body is critical. Disruptions of axonal transport are thought to contribute to the pathologies of Alzheimer's, amyotrophic lateral sclerosis, and other neurodegenerative diseases (reviewed by Mandelkow and Mandelkow, 2002;Hirokawa and Takemura, 2005).Long-distance organelle transport in axons is driven by motor proteins that move along parallel microtubules whose plus ends are mostly oriented toward the axon terminal (reviewed by Hollenbeck and Saxton, 2005). There are multiple types of microtubule motors in postmitotic vertebrate neurons, including kinesins that can move toward either plus-or minus-ends and at least one cytoplasmic dynein that moves toward minus-ends (Martin et al., 1999b;Hirokawa and Takemura, 2005;Hollenbeck and Saxton, 2005). Which motors bind and move which axonal components? When multiple types of motors bind a single cargo, do they collaborate or compete, how are they regulated, and how do their combined activities generate an optimal distribution of that type of cargo?Axonal mitochondria are critical for the physiology of neurons and are particularly well suited for studying active tr...

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Section: Motors For Axonal Transport Of Mitochondriamentioning

confidence: 66%

Kinesin-1 and Dynein Are the Primary Motors for Fast Transport of Mitochondria inDrosophilaMotor Axons

Pilling

Horiuchi

Lively

et al. 2006

MBoC

615

621

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“…Palmer et al [14] reported that depleting DLIC1 by RNAi in HeLa cells disrupted the Golgi apparatus, but Sivaram et al [11] claimed that it had no effect on the Golgi. Mutating Dlic gene blocks the transport of neuronal retrograde cargoes in worms and flies [16][17][18] and results in dendritic and axonal defects in neurons, such as a reduction in the length and number of dendrite branches in Drosophila. However, mice with a point mutation Dlic1 N235Y display an increase in dendrite length of cortical neurons (with no changes in branching) and the number of dendrite branches of dorsal root ganglia (DRG) neurons, in addition to its increased anxiety-like behavior and altered gait [19].…”

Section: Introductionmentioning

confidence: 99%

Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

Kong

Peng

et al. 2013

Cell Res

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Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells. However, in mammals, few mutants are available for studying the effects of defects in dynein-controlled processes in the context of the whole organism. Here, we deleted mouse Dlic1 gene encoding DLIC1, a subunit of the dynein complex. Dlic1 −/− mice are viable, but display severe photoreceptor degeneration. Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins, and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rab11-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body. Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER), but seems not to affect vesicle transport from the ER to Golgi. Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors, probably due to the impaired transport function of dynein. Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS, and is required for photoreceptor development and survival. The Dlic1 −/− mice also provide a new mouse model to study human retinal degeneration.

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“…Our time-lapse imaging experiments showed that DLK-1(K162A) puncta moved both anterogradely and retrogradely (Fig. 4D) and that the retrograde DLK-1 movements were abolished by a temperature-sensitive mutation in dhc-1, the cytoplasmic dynein heavy chain (33)(34)(35) (Fig. 4D).…”

Section: Dlk-1 Retrograde Signaling Contributes To Plm Branch Defectsmentioning

confidence: 92%

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

Chen

Lee

Liao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurons remodel their connectivity in response to various insults, including microtubule disruption. How neurons sense microtubule disassembly and mount remodeling responses by altering genetic programs in the soma are not well defined. Here we show that in response to microtubule disassembly, the Caenorhabditis elegans PLM neuron remodels by retracting its synaptic branch and overextending the primary neurite. This remodeling required RHGF-1, a PDZ-Rho guanine nucleotide exchange factor (PDZ-RhoGEF) that was associated with and inhibited by microtubules. Independent of the myosin light chain activation, RHGF-1 acted through Rho-dependent kinase LET-502/ROCK and activated a conserved, retrograde DLK-1 MAPK (DLK-1/dual leucine zipper kinase) pathway, which triggered synaptic branch retraction and overgrowth of the PLM neurite in a dose-dependent manner. Our data represent a neuronal remodeling paradigm during development that reshapes the neural circuit by the coordinated removal of the dysfunctional synaptic branch compartment and compensatory extension of the primary neurite.axon retraction | axon regeneration | Rho signaling | DLK | microtubules T he connectivity of neuronal circuits is established first through a highly dynamic phase of addition or elimination of axon branches and synapses, followed by a maintenance phase in which axon and dendritic branches show remarkable stability during the lifetime of postmitotic neurons. Disruption of neuronal circuits elicits remodeling responses that eliminate dysfunctional neurites or synapses and may stimulate the regeneration of injured axons. To enable these remodeling responses, neurons need to sense the insults and signal to the effectors that execute either retraction or extension of the neuronal structures. A well-studied effector for neuronal remodeling is the dual leucine-zipper kinase DLK, whose activation is required for both Wallerian degeneration and axon regeneration after injury, depending on the species and contexts examined (1-4). The DLK protein level is primarily controlled by proteasomal turnover that depends on Highwire/RPM-1, a ubiquitin E3 ligase that targets DLK for degradation (5). The Caenorhabditis elegans DLK, DLK-1, is activated by calcium influx during axon injury that triggers the dissociation of an inhibitory DLK-1 isoform (6). A recent report suggests that C. elegans dlk-1 is a direct transcriptional target of the FoxO transcription factor DAF-16 in axon regeneration (7). Despite the extensive characterization of DLK, little is known about how neurons sense various insults and translate them into DLK-activating signals.Microtubules are a major neuronal cytoskeleton component that shapes and maintains synapses and axons (8, 9). Mutations in Ankyrin and α-spectrin, two membrane skeletal proteins that organize microtubules at presynaptic sites, triggered synaptic bouton shrinkage and axon terminal retraction at Drosophila neuromuscular junction, highlighting the central importance of microtubules in the maintenance of synapses and axon b...

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Mutations inCaenorhabditis elegansCytoplasmic Dynein Components Reveal Specificity of Neuronal Retrograde Cargo

Cited by 100 publications

References 67 publications

Kinesin-1 and Dynein Are the Primary Motors for Fast Transport of Mitochondria inDrosophilaMotor Axons

Kinesin-1 and Dynein Are the Primary Motors for Fast Transport of Mitochondria inDrosophilaMotor Axons

Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

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