A Lipid-TORC1 Pathway Promotes Neuronal Development and Foraging Behavior under Both Fed and Fasted Conditions in C. elegans

Axon specification is a critical step in neuronal development, and the function of glial cells in this process is not fully understood. Here, we show that C. elegans GLR glial cells regulate axon specification of their nearby GABAergic RME neurons through GLR-RME gap junctions. Disruption of GLR-RME gap junctions causes misaccumulation of axonal markers in non-axonal neurites of RME neurons and converts microtubules in those neurites to form an axon-like assembly. We further uncover that GLR-RME gap junctions regulate RME axon specification through activation of the CDK-5 pathway in a calcium-dependent manner, involving a calpain clp-4. Therefore, our study reveals the function of glia-neuron gap junctions in neuronal axon specification and shows that calcium originated from glial cells can regulate neuronal intracellular pathways through gap junctions.

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Investigating the Roles of RNA Binding Protein Combinations in Neuronal Function and Organismal Behavior

10.25172/jour.4.1.7 ◽

2019 ◽

Vol 4 (Spring 2019) ◽

Author(s):

Alexa Vandenburg

Keyword(s):

Binding Sites ◽

Neuronal Development ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Wild Type ◽

C Elegans ◽

Neuronal Gene ◽

Touch Response

The Norris lab recently identified two RNA binding proteins required for proper neuron-specific splicing. The lab conducted touch- response behavioral assays to assess the function of these proteins in touch-sensing neurons. After isolating C. elegans worms with specific phenotypes, the lab used automated computer tracking and video analysis to record the worms’ behavior. The behavior of mutant worms differed from that of wild-type worms. The Norris lab also discovered two possible RNA binding protein sites in SAD-1, a neuronal gene implicated in the neuronal development of C. elegans1. These two binding sites may control the splicing of SAD-1. The lab transferred mutated DNA into the genome of wild-type worms by injecting a mutated plasmid. The newly transformed worms fluoresced green, indicating that the two binding sites control SAD-1 splicing.

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C. elegans CARMIL negatively regulates UNC-73/Trio function during neuronal development

Development ◽

10.1242/dev.026666 ◽

2009 ◽

Vol 136 (7) ◽

pp. 1201-1210 ◽

Cited By ~ 24

Author(s):

P. J. Vanderzalm ◽

A. Pandey ◽

M. E. Hurwitz ◽

L. Bloom ◽

H. R. Horvitz ◽

...

Keyword(s):

Neuronal Development ◽

C Elegans

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Laterally Orienting C. elegans Using Geometry at Microscale for High-Throughput Visual Screens in Neurodegeneration and Neuronal Development Studies

PLoS ONE ◽

10.1371/journal.pone.0035037 ◽

2012 ◽

Vol 7 (4) ◽

pp. e35037 ◽

Cited By ~ 40

Author(s):

Ivan de Carlos Cáceres ◽

Nicholas Valmas ◽

Massimo A. Hilliard ◽

Hang Lu

Keyword(s):

High Throughput ◽

Neuronal Development ◽

Development Studies ◽

C Elegans

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Microtubule-dependent ribosome localization in C. elegans neurons

eLife ◽

10.7554/elife.26376 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 16

Author(s):

Kentaro Noma ◽

Alexandr Goncharov ◽

Mark H Ellisman ◽

Yishi Jin

Keyword(s):

Cell Biology ◽

Neuronal Development ◽

Ultrastructural Level ◽

Synthesis Methods ◽

Tissue Specific ◽

C Elegans ◽

Multicellular Organisms ◽

Axonal Trafficking ◽

Insight Into

Subcellular localization of ribosomes defines the location and capacity for protein synthesis. Methods for in vivo visualizing ribosomes in multicellular organisms are desirable in mechanistic investigations of the cell biology of ribosome dynamics. Here, we developed an approach using split GFP for tissue-specific visualization of ribosomes in Caenorhabditis elegans. Labeled ribosomes are detected as fluorescent puncta in the axons and synaptic terminals of specific neuron types, correlating with ribosome distribution at the ultrastructural level. We found that axonal ribosomes change localization during neuronal development and after axonal injury. By examining mutants affecting axonal trafficking and performing a forward genetic screen, we showed that the microtubule cytoskeleton and the JIP3 protein UNC-16 exert distinct effects on localization of axonal and somatic ribosomes. Our data demonstrate the utility of tissue-specific visualization of ribosomes in vivo, and provide insight into the mechanisms of active regulation of ribosome localization in neurons.

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C. elegans PVD Neurons: A Platform for Functionally Validating and Characterizing Neuropsychiatric Risk Genes

10.1101/053900 ◽

2016 ◽

Author(s):

Cristina Aguirre-Chen ◽

Nuri Kim ◽

Olivia Mendivil Ramos ◽

Melissa Kramer ◽

W. Richard McCombie ◽

...

Keyword(s):

Protein Function ◽

Molecular Mechanisms ◽

Neuronal Development ◽

De Novo ◽

Genetic Interaction ◽

Cost Effective ◽

Chromatin Remodelers ◽

C Elegans ◽

Effective Manner

AbstractOne of the primary challenges in the field of psychiatric genetics is the lack of an in vivo model system in which to functionally validate candidate neuropsychiatric risk genes (NRGs) in a rapid and cost-effective manner1−3. To overcome this obstacle, we performed a candidate-based RNAi screen in which C. elegans orthologs of human NRGs were assayed for dendritic arborization and cell specification defects using C. elegans PVD neurons. Of 66 NRGs, identified via exome sequencing of autism (ASD)4 or schizophrenia (SCZ)5−9 probands and whose mutations are de novo and predicted to result in a complete or partial loss of protein function, the C. elegans orthologs of 7 NRGs were found to be required for proper neuronal development and represent a variety of functional classes, including transcriptional regulators and chromatin remodelers, molecular chaperones, and cytoskeleton-related proteins. Notably, the positive hit rate, when selectively assaying C. elegans orthologs of ASD and SCZ NRGs, is enriched >14-fold as compared to unbiased RNAi screening10. Furthermore, we find that RNAi phenotypes associated with the depletion of NRG orthologs is recapitulated in genetic mutant animals, and, via genetic interaction studies, we show that the NRG ortholog of ANK2, unc-44, is required for SAX-7/MNR-1/DMA-1 signaling. Collectively, our studies demonstrate that C. elegans PVD neurons are a tractable model in which to discover and dissect the fundamental molecular mechanisms underlying neuropsychiatric disease pathogenesis.

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The Amyloid Precursor-like Protein APL-1 Regulates Axon Regeneration

10.1101/305284 ◽

2018 ◽

Cited By ~ 2

Author(s):

Lewie Zeng ◽

Rachid El Bejjani ◽

Marc Hammarlund

Keyword(s):

Motor Neurons ◽

Neuronal Development ◽

Axon Regeneration ◽

Neuronal Response ◽

Small Gtpase ◽

C Elegans ◽

Protein Levels ◽

Mature Neurons ◽

And Function

AbstractMembers of the Amyloid Precursor Protein (APP) family have important functions during neuronal development. However, their physiological functions in the mature nervous system are not fully understood. Here we use the C. elegans GABAergic motor neurons to study the post-developmental function of the APP-like protein APL-1 in vivo. We find that apl-1 has minimum roles in the maintenance of gross neuron morphology and function. However, we show that apl-1 is an inhibitor of axon regeneration, acting on mature neurons to limit regrowth in response to injury. The small GTPase Rab6/RAB-6.2 also inhibits regeneration, and does so in part by maintaining protein levels of APL-1. To inhibit regeneration, APL-1 functions via the E2 domain of its ectodomain; the cytoplasmic tail, transmembrane anchoring, and the E1 domain are not required for this function. Our data defines a novel role for APL-1 in modulating the neuronal response to injury.

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Faculty Opinions recommendation of Laterally orienting C. elegans using geometry at microscale for high-throughput visual screens in neurodegeneration and neuronal development studies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.715947820.791452802 ◽

2012 ◽

Author(s):

Oliver Hobert ◽

Oded Rechavi

Keyword(s):

High Throughput ◽

Neuronal Development ◽

Development Studies ◽

C Elegans

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Multiple Roles of RNA Regulatory Factors in Neuronal Development and Function in C. elegans

The Oxford Handbook of Neuronal Protein Synthesis ◽

10.1093/oxfordhb/9780190686307.013.26 ◽

2020 ◽

Author(s):

Matthew G. Andrusiak ◽

Yishi Jin

Keyword(s):

Nervous System ◽

Cell Biology ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Rna Binding ◽

Rna Binding Proteins ◽

Model Organism ◽

Nervous System Development ◽

Forward Genetics ◽

C Elegans

Recent evidence has highlighted the dynamic nature of mRNA regulation, particularly in the nervous system, from complex pre-mRNA processing to long-range transport and long-term storage of mature mRNAs. In accordance with the importance for mRNA-mediated regulation of nervous system development and maintenance, various mutations in RNA-binding proteins are associated with a range of human disorders. C. elegans express many RNA-binding factors that have human orthologs and perform similar biochemical functions. This chapter focuses on the research using C. elegans to dissect molecular mechanisms involving mRNA-mediated pathways. It highlights the key approaches and findings that integrate genetic and genomic studies in the nervous system. The analyses of genetic mutants, primarily using forward genetics, offer functional insights for genes important for neuronal development, synaptic transmission, and neuronal repair. In combination with single-neuron cell biology and cell-type genomics, the knowledge learned from this model organism has continued to lead to ground-breaking discoveries.

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Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans

Molecular Biology of the Cell ◽

10.1091/mbc.e17-06-0424 ◽

2017 ◽

Vol 28 (21) ◽

pp. 2786-2801 ◽

Cited By ~ 8

Author(s):

Chaogu Zheng ◽

Margarete Diaz-Cuadros ◽

Ken C. Q. Nguyen ◽

David H. Hall ◽

Martin Chalfie

Keyword(s):

Caenorhabditis Elegans ◽

Neuronal Development ◽

Function Analysis ◽

Critical Role ◽

Neurite Growth ◽

Cellular Level ◽

Missense Mutations ◽

Loss Of Function ◽

Exterior Surface ◽

C Elegans

Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization.

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