Microtubule depolymerization in
            <i>Caenorhabditis elegans</i>
            touch receptor neurons reduces gene expression through a p38 MAPK pathway

Bounoutas, Alexander; Kratz, John Ernest; Emtage, Lesley; Ma, Charles; Nguyen, Ken; Chalfie, Martin

doi:10.1073/pnas.1101360108

Cited by 85 publications

(90 citation statements)

References 51 publications

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“…The parallel DLK-1 and MLK-1 pathways activating PMK-3(p38) and KGB-1(JNK) may also be relevant to the studies demonstrating a role for DLK in regulating axon degeneration in Drosophilia (30) and microtubule regulated gene expression in C. elegans (44). The model proposed by Bounoutas et al suggests that an unknown MAPKK may activate PMK-3 in parallel to MKK-4 (44).…”

Section: Discussionmentioning

confidence: 99%

Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways

Nix

Hisamoto

Matsumoto

et al. 2011

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

179

205

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Signaling pathways essential for axon regeneration, but not for neuron development or function, are particularly well suited targets for therapeutic intervention. We find that the parallel PMK-3(p38) and KGB-1(JNK) MAPK pathways must be coordinately activated to promote axon regeneration. Axon regeneration fails if the activity of either pathway is absent. These two MAPKs are coregulated by the E3 ubiquitin ligase RPM-1(Phr1) via targeted degradation of the MAPKKKs DLK-1 and MLK-1 and by the MAPK phosphatase VHP-1(MKP7), which negatively regulates both PMK-3 (p38) and KGB-1(JNK).Caenorhabditis elegans | MAPK signaling | laser axotomy N euronal regeneration has been studied in humans and other animal model systems for over 100 years, yet we still do not have a comprehensive molecular model or an effective treatment for axotomy due to injury or disease (1-9). In vivo and in vitro model systems have been developed to focus on identifying the molecular differences between vertebrate neurons that can and cannot regenerate (e.g., PNS versus CNS and embryonic versus adult), or between animals that exhibit major differences in their regenerative capacities (e.g., salamander versus mouse). Many exciting discoveries have been made that illustrate the importance of both the extracellular molecular environment and the intrinsic cellular "state" of the neuron (10-13). Classic experiments showing that adult CNS neurons can indeed regenerate if given the right environment, and the identification of many inhibitory molecules associated with CNS myelin and the glial scar stand out as turning points reigniting interest in potential therapies for spinal injury (4,14). Genetic and cellular studies identifying genes regulating neuron development, motility, and pathfinding have added to the excitement and provided many new environmental and cell intrinsic molecular signaling pathways as potential regulators of neural regeneration (2).In 2004, laser axotomy was introduced to Caenorhabditis elegans by Yanik et al. (15), who showed for the first time that axon regeneration in this model system is robust. Subsequent studies by several laboratories have described the similar features of axon regeneration in C. elegans compared with mammals, and provided some insights into the genetic basis of axon regeneration (16-21). The development of microfluidic chambers to automate the immobilization of worms, combined with laser axotomy, raises the hope for high throughput axon regeneration screening assays (22-25). We made an observation that makes it possible to screen for genes that affect axon regeneration in C. elegans without laser axotomy (26). We discovered that embryonic neurons lacking β-spectrin develop normally but, after hatching, undergo a spontaneous movement-induced axotomy followed by regeneration. Most commissural axons in each animal break and regenerate before the animal reaches adulthood.In a previous study, we identified the MAPKKK DLK-1 in our unc-70(β-spectrin) based RNAi screen for genes required for axon regeneration in C....

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Section: Discussionmentioning

confidence: 99%

Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways

Nix

Hisamoto

Matsumoto

et al. 2011

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

179

205

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“…For example, two new alleles of pmk-3, ju1010 and ju592, are nonsense mutations after the kinase domain, suggesting that the C terminus of PMK-3 may regulate the protein activity or stability. cebp-1(ju634) altered arginine 63 to proline in the N terminus of the protein, whereas the majority of the previously reported cebp-1 mutations affect the bZip domain (Yan et al 2009;Bounoutas et al 2011) ( Figure 2D and Table S1). In summary, 98% of the suppressor mutations identified in our screens affected the six genes of the DLK-1 kinase cascade ( Figure 2A and Table S1), and the number of the identified alleles roughly correlated with the size of the coding regions of the genes ( Figure 2B).…”

mentioning

confidence: 87%

Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

2014

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The PHR (Pam/Highwire/RPM-1) family of ubiquitin E3 ligases plays conserved roles in axon patterning and synaptic development. Genetic modifier analysis has greatly aided the discovery of the signal transduction cascades regulated by these proteins. In Caenorhabditis elegans, loss of function in rpm-1 causes axon overgrowth and aberrant presynaptic morphology, yet the mutant animals exhibit little behavioral deficits. Strikingly, rpm-1 mutations strongly synergize with loss of function in the presynaptic active zone assembly factors, syd-1 and syd-2, resulting in severe locomotor deficits. Here, we provide ultrastructural evidence that double mutants, between rpm-1 and syd-1 or syd-2, dramatically impair synapse formation. Taking advantage of the synthetic locomotor defects to select for genetic suppressors, previous studies have identified the DLK-1 MAP kinase cascade negatively regulated by RPM-1. We now report a comprehensive analysis of a large number of suppressor mutations of this screen. Our results highlight the functional specificity of the DLK-1 cascade in synaptogenesis. We also identified two previously uncharacterized genes. One encodes a novel protein, SUPR-1, that acts cell autonomously to antagonize RPM-1. The other affects a conserved protein ESS-2, the homolog of human ES2 or DGCR14. Loss of function in ess-2 suppresses rpm-1 only in the presence of a dlk-1 splice acceptor mutation. We show that ESS-2 acts to promote accurate mRNA splicing when the splice site is compromised. The human DGCR14/ES2 resides in a deleted chromosomal region implicated in DiGeorge syndrome, and its mutation has shown high probability as a risk factor for schizophrenia. Our findings provide the first functional evidence that this family of proteins regulate mRNA splicing in a context-specific manner. P ROPER synapse development ensures precise wiring and efficient transmission of information in the nervous system. In the presynaptic terminals, dense and organized accumulation of synaptic vesicles around the docking site called active zone is essential for rapid release of neurotransmitters (Sudhof 2012). Forward genetic screens in Caenorhabditis elegans, aided by visualization of synapse morphology using fluorescent reporters, have made important contributions to uncover conserved genes and pathways regulating presynaptic assembly (Jin and Garner 2008;Ou and Shen 2010). Many such screens have identified a common set of genes that regulate specific aspects of presynaptic differentiation in many neurons (Ackley and Jin 2004;Jin 2005;Maeder and Shen 2011). Among them are SYD-2/a-Liprin (LAR interacting protein), which has a central role in presynaptic active zone formation (Zhen and Jin 1999;Dai et al. 2006); SYD-1, a PDZ-RhoGAP protein that acts upstream of SYD-2 (Patel and Shen 2009;Hallam et al. 2002); and RPM-1, an E3 ubiquitin ligase that regulates synaptic organization (Schaefer et al. 2000;Zhen et al. 2000).Despite their strong defects in synaptic morphology, single loss-of-function (lf) mutants of rpm-1...

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“…However, how microtubules coordinate structural stability and remodeling of neurons under insults remains incompletely understood. Genetic or pharmacologic ablation of microtubules in the C. elegans touch neurons reduced the expression of several touch neuron-specific genes through the activation of the DLK-1 MAPK pathway (14). Because DLK-1 is a major effector for neuronal remodeling, taken together, these studies raise the possibility that microtubule disruption drives neuronal remodeling through DLK-1 activation.…”

mentioning

confidence: 91%

“…Genetic or pharmacologic ablation of microtubules in C. elegans activates dlk-1, a MAPKKK (14). It had been reported that rpm-1 mutants, which had high dlk-1 activity, lost PLM branches (30).…”

Section: Dlk-1/mapk Functions Downstream Of Rhgf-1 In Plm Remodeling Onmentioning

confidence: 99%

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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Microtubule depolymerization in Caenorhabditis elegans touch receptor neurons reduces gene expression through a p38 MAPK pathway

Cited by 85 publications

References 51 publications

Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways

Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways

Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

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

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