Genes Required for Cellular UNC-6/Netrin Localization in <i>Caenorhabditis elegans</i>

Asakura, Taro; Waga, Naoko; Ogura, Ken-ichi; Goshima, Yoshio

doi:10.1534/genetics.110.116293

Cited by 19 publications

(33 citation statements)

References 88 publications

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“…We found that unc-17(e245), unc-104(e1265), or cha-1(p1152) enhances the AVM ventral axon guidance defect caused by slt-1(eh15), which suggests that acetylcholine potentiates UNC-6-mediated axon guidance ( Figure 2D). Our results are similar to those previously reported for unc-104(e1265) (Asakura et al 2010).…”

Section: Resultssupporting

confidence: 93%

“…In fact, a recent study provides evidence that UNC-104 might be required for UNC-6 secretion (Asakura et al 2010). In this study, a Venus-tagged UNC-6 showed a punctate distribution pattern throughout the cytoplasm and axons of wild-type neurons, but in unc-104 (e1265) mutants the UNC-6 was observed evenly distributed in the cell body with little detected in the axon.…”

Section: Resultsmentioning

confidence: 55%

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Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis elegans

Ren²,

Quinn

et al. 2011

Genetics

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Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in culture, and it has been suggested that acetylcholine could act as a guidance cue. However, the role acetylcholine plays in directing axon migrations in vivo is not clear. Here, we show that acetylcholine positively regulates signaling pathways that mediate axon responses to guidance cues in Caenorhabditis elegans. Mutations that disrupt acetylcholine synthesis, transportation, and secretion affect circumferential axon guidance of the AVM neuron and in these mutants exogenously supplied acetylcholine improves AVM circumferential axon guidance. These effects are not observed for the circumferential guidance of the DD and VD motor neuron axons, which are neighbors of the AVM axon. Circumferential guidance is directed by the UNC-6 (netrin) and SLT-1 (slit) extracellular cues, and exogenously supplied acetylcholine can improve AVM axon guidance in mutants when either UNC-6-or SLT-1-induced signaling is disrupted, but not when both signaling pathways are perturbed. Not in any of the mutants does exogenously supplied acetylcholine improve DD and VD axon guidance. The ability of acetylcholine to enhance AVM axon guidance only in the presence of either UNC-6 or SLT-1 indicates that acetylcholine potentiates UNC-6 and SLT-1 guidance activity, rather than acting itself as a guidance cue. Together, our results show that for specific neurons acetylcholine plays an important role in vivo as a modulator of axon responses to guidance cues. C ELLS secrete molecules that help guide axon growth cone migrations. In Caenorhabditis elegans, UNC-6 (netrin) and SLT-1 (slit) are secreted guidance cues and are ligands for the UNC-40 (DCC) and SAX-3 (Robo) receptors, which are present at the surface of the migrating axons (Hedgecock et al.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 55%

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis elegans

Ren²,

Quinn

et al. 2011

Genetics

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“…5A-C; P<0.0001), suggesting that only a small fraction of TIR-l was localized to puncta in the AWC axons in unc-104(e1265) mutants compared with wild type. Unlike synaptic vesicles, dense core vesicles and UNC-6/netrin [which were shown to accumulate in the cell body and dendrites of unc-104 mutants (Asakura et al, 2010;Hall and Hedgecock, 1991;Nonet, 1999;Ou et al, 2010;Zahn et al, 2004)], TIR-1 was not detected in the AWC cell body or dendrites in unc-104 mutants. These results suggest that unc-104 may be required for the stability of TIR-1 protein, similar to the function of kinesin KIF4 in regulating intracellular trafficking and stability of HIV-1 Gag polyprotein (Martinez et al, 2008).…”

Section: Research Articlementioning

confidence: 97%

Microtubule-based localization of a synaptic calcium-signaling complex is required for left-right neuronal asymmetry in C. elegans

et al. 2011

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SUMMARYThe axons of C. elegans left and right AWC olfactory neurons communicate at synapses through a calcium-signaling complex to regulate stochastic asymmetric cell identities called AWC ON and AWC OFF . However, it is not known how the calcium-signaling complex, which consists of UNC-43/CaMKII, TIR-1/SARM adaptor protein and NSY-1/ASK1 MAPKKK, is localized to postsynaptic sites in the AWC axons for this lateral interaction. Here, we show that microtubule-based localization of the TIR-1 signaling complex to the synapses regulates AWC asymmetry. Similar to unc-43, tir-1 and nsy-1 loss-of-function mutants, specific disruption of microtubules in AWC by nocodazole generates two AWC ON neurons. Reduced localization of UNC-43, TIR-1 and NSY-1 proteins in the AWC axons strongly correlates with the 2AWC ON phenotype in nocodazole-treated animals. We identified kinesin motor unc-104/kif1a mutants for enhancement of the 2AWC ON phenotype of a hypomorphic tir-1 mutant. Mutations in unc-104, like microtubule depolymerization, lead to a reduced level of UNC-43, TIR-1 and NSY-1 proteins in the AWC axons. In addition, dynamic transport of TIR-1 in the AWC axons is dependent on unc-104, the primary motor required for the transport of presynaptic vesicles. Furthermore, unc-104 acts non-cell autonomously in the AWC ON neuron to regulate the AWC OFF identity. Together, these results suggest a model in which UNC-104 may transport some unknown presynaptic factor(s) in the future AWC ON cell that non-cell autonomously control the trafficking of the TIR-1 signaling complex to postsynaptic regions of the AWC axons to regulate the AWC OFF identity.

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“…1c). Therefore, previous screens that identified mutants focusing on one trait (such as synaptic localization)5657, or based on qualitative inspection, must have relied on favourable sampling of these populations (either by having screened more than one animal from these genotypes or by having stochastically sampled a phenotypically severe individual); in other words, many alleles could have been missed in these screens, and even in the screens for severe phenotypic changes.…”

Section: Resultsmentioning

confidence: 99%

Deep phenotyping unveils hidden traits and genetic relations in subtle mutants

et al. 2016

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Discovering mechanistic insights from phenotypic information is critical for the understanding of biological processes. For model organisms, unlike in cell culture, this is currently bottlenecked by the non-quantitative nature and perceptive biases of human observations, and the limited number of reporters that can be simultaneously incorporated in live animals. An additional challenge is that isogenic populations exhibit significant phenotypic heterogeneity. These difficulties limit genetic approaches to many biological questions. To overcome these bottlenecks, we developed tools to extract complex phenotypic traits from images of fluorescently labelled subcellular landmarks, using C. elegans synapses as a test case. By population-wide comparisons, we identified subtle but relevant differences inaccessible to subjective conceptualization. Furthermore, the models generated testable hypotheses of how individual alleles relate to known mechanisms or belong to new pathways. We show that our model not only recapitulates current knowledge in synaptic patterning but also identifies novel alleles overlooked by traditional methods.

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Genes Required for Cellular UNC-6/Netrin Localization in Caenorhabditis elegans

Cited by 19 publications

References 88 publications

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis elegans

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis elegans

Microtubule-based localization of a synaptic calcium-signaling complex is required for left-right neuronal asymmetry in C. elegans

Deep phenotyping unveils hidden traits and genetic relations in subtle mutants

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