A Ubiquitin E2 Variant Protein Acts in Axon Termination and Synaptogenesis in <i>Caenorhabditis elegans</i>

Trujillo, Gloriana; Nakata, Katsunori; Yan, Dong; Maruyama, Ichiro; Jin, Yishi

doi:10.1534/genetics.110.117341

Cited by 19 publications

(29 citation statements)

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“…In rpm-1(lf) mutants the Posterior Lateral Microtubule (PLM) neurons display highly penetrant axon overshooting and frequent absence of synaptic branches (Schaefer et al 2000) (Figure 3, B-D). These PLM axon developmental defects of rpm-1(lf) are completely suppressed by loss-of-function mutations in the DLK-1 cascade (Yan et al 2009;Trujillo et al 2010) (Figure 3,C and D). In contrast, null mutations in mlk-1, mek-1, or kgb-1 showed rather mild suppression (Figure 3,C and D).…”

Section: Resultsmentioning

confidence: 98%

“…We previously reported multiple rpm-1 suppressors that cause loss of function in components of the DLK-1/MKK-4/PMK-3 MAP kinase pathway ( Figure 2A and Figure S2) (Nakata et al 2005;Yan et al 2009;Trujillo et al 2010). We therefore devised a complementation workflow to test whether new suppressors affected these known genes…”

Section: Most Suppressors Of the Developmental Defects Of Rpm-1 Affecmentioning

confidence: 99%

“…This synthetic behavioral deficit of double mutants has allowed powerful selections for genetic suppressor mutations. Previous characterization of multiple rpm-1(lf) suppressors uncovered the DLK-1 MAP kinase pathway, consisting of dlk-1/MAPKKK, mkk-4/MAPKK, pmk-3/ MAPK, and mak-2/MAPKAP2, uev-3/E2 ubiquitin-conjugating enzyme variant, and cebp-1, a bZip-domain transcription factor acting downstream of the DLK-1 kinase cascade (Nakata et al 2005;Yan et al 2009;Trujillo et al 2010). Further analysis of specific DLK-1 missense alterations also provided key insights into the mechanism of DLK-1 activation (Yan and Jin 2012).…”

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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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Section: Resultsmentioning

confidence: 98%

Section: Most Suppressors Of the Developmental Defects Of Rpm-1 Affecmentioning

confidence: 99%

mentioning

confidence: 99%

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

2014

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“…In some cases these signals indicate to a migrating axon to transition from a migratory, non-synapse forming growth cone to an adherent synapse forming axon. Synapse formation and axon extension are also linked in C. elegans (Grill et al, 2007; Yan et al, 2009; Trujillo et al, 2010). VD neurons are born at the late L1 larval stage, and their neurites increase ~3–5 fold in length by the time the animal reaches the adulthood.…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegansFlamingo Cadherinfmi-1Regulates GABAergic Neuronal Development

Najarro¹,

Wong²,

Zhen³

et al. 2012

J. Neurosci.

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In a genetic screen for regulators of synaptic morphology, we identified the single C. elegans flamingo-like cadherin fmi-1. fmi-1 mutants exhibit defective axon pathfinding, reduced synapse number, aberrant synapse size and morphology, as well as an abnormal accumulation of synaptic vesicles at non-synaptic regions. Although FMI-1 is primarily expressed in the nervous system, it is not expressed in the Ventral D-type (VD) GABAergic motorneurons, which are defective in fmi-1 mutants. The axon and synaptic defects of VD neurons could be rescued when fmi-1 was expressed exclusively in non-VD, neighboring neurons, suggesting a cell non-autonomous action of FMI-1. FMI-1 protein that lacked its intracellular domain still retained its ability to rescue the vesicle accumulation defects of GABAergic motorneurons, indicating that the extracellular domain (ECD) was sufficient for this function of FMI-1 in GABAergic NMJ development. Mutations in cdh-4, a Fat-like cadherin, cause similar defects in GABAergic motorneurons. cdh-4 is expressed by the VD neurons, and appears to function in the same genetic pathway as fmi-1 to regulate GABAergic neuron development. Thus, fmi-1 and cdh-4 cadherins might act together to regulate synapse development and axon pathfinding.

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“…In C. elegans , RPM-1 acts cell-autonomously in the PLM mechanosensory neuron and DA/DB motorneurons to regulate axon termination, guidance, and synapse formation (Grill et al 2007; Li et al 2008; Trujillo et al 2010; Tulgren et al 2011). Consistent with these observations, the rpm-1 mutants, including both existent alleles and those isolated in our screen, exhibited failure of the M1 terminal process to stop at their final destination.…”

Section: Discussionmentioning

confidence: 99%

Extension of theCaenorhabditis elegansPharyngeal M1 Neuron Axon Is Regulated by Multiple Mechanisms

Refai

Rohs

Mains

et al. 2013

G3 Genes|Genomes|Genetics

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The guidance of axons to their correct targets is a critical step in development. The C. elegans pharynx presents an attractive system to study neuronal pathfinding in the context of a developing organ. The worm pharynx contains relatively few cells and cell types, but each cell has a known lineage and stereotyped developmental patterns. We found that extension of the M1 pharyngeal axon, which spans the entire length of the pharynx, occurs in two distinct phases. The first proximal phase does not require genes that function in axon extension (unc-34, unc-51, unc-115, and unc-119), whereas the second distal phase does use these genes and is guided in part by the adjacent g1P gland cell projection. unc-34, unc-51, and unc-115 had incompletely penetrant defects and appeared to act in conjunction with the g1P cell for distal outgrowth. Only unc-119 showed fully penetrant defects for the distal phase. Mutations affecting classical neuronal guidance cues (Netrin, Semaphorin, Slit/Robo, Ephrin) or adhesion molecules (cadherin, IgCAM) had, at best, weak effects on the M1 axon. None of the mutations we tested affected the proximal phase of M1 elongation. In a forward genetic screen, we isolated nine mutations in five genes, three of which are novel, showing defects in M1, including axon overextension, truncation, or ectopic branching. One of these mutations appeared to affect the generation or differentiation of the M1 neuron. We conclude that M1 axon extension is a robust process that is not completely dependent on any single guidance mechanism.

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A Ubiquitin E2 Variant Protein Acts in Axon Termination and Synaptogenesis in Caenorhabditis elegans

Cited by 19 publications

References 50 publications

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

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

Caenorhabditis elegansFlamingo Cadherinfmi-1Regulates GABAergic Neuronal Development

Extension of theCaenorhabditis elegansPharyngeal M1 Neuron Axon Is Regulated by Multiple Mechanisms

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