A Putative Cation Channel, NCA-1, and a Novel Protein, UNC-80, Transmit Neuronal Activity in C. elegans

Yeh, Edward T.H.; Ng, S. C.; Zhang, Mi; Bouhours, Magali; Wang, Ying; Wang, Min; Hung, Wesley; Aoyagi, Kyota; Melnik-Martinez, Katya; Li, Michelle; Liu, Fang; Schafer, William R.; Zhen, Mei

doi:10.1371/journal.pbio.0060055

Cited by 116 publications

(209 citation statements)

References 45 publications

(80 reference statements)

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“…Our promoter analysis suggests that unc-79 and unc-80 are co-expressed in neurons, consistent with the overlapping neural expression of their mouse orthologues (28). UNC-79 was also found to stabilize expression of UNC-80 and vice versa in C. elegans (16). Thus, UNC-79 and UNC-80 might function together in the nervous system in mammals as well as in invertebrates.…”

Section: Discussionsupporting

confidence: 80%

“…UNC-79 and UNC-80 were recently found necessary for stability of NCA-type channels in C. elegans and in Drosophila species (13,15,16). mRNA of the unc-80 orthologue is reported to be enriched in neural tissue in both mouse and human (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…The fainter phenotype has been attributed to lack of a novel class of NCA-type ion channel because the nca-1;nca-2 double mutant shares the fainter phenotype and unc-79 and unc-80 mutants have undetectable levels of NCA-1 and NCA-2 ion channels (16). The mammalian NCA channel orthologue (NALCN) has recently been functionally characterized as a sodium ''leak'' channel that acts to raise resting potential greater than the equilibrium potential for potassium (14).…”

Section: Genetic Screen For Mutants Defective In Transitioning From Cmentioning

confidence: 99%

“…We provide evidence from analysis of sensory mutants that maintenance of swimming, rather than crawl-like behavior in liquid, requires sensory input. We then performed a genetic screen to identify a set of molecules from a recently described putative nematode cation channel (NCA) (13)(14)(15)(16) that is crucial for the swimming form of locomotion.…”

mentioning

confidence: 99%

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Genetic analysis of crawling and swimming locomotory patterns in C. elegans

Pierce-Shimomura

Chen

Mun

et al. 2008

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

250

265

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Alternative patterns of neural activity drive different rhythmic locomotory patterns in both invertebrates and mammals. The neuro-molecular mechanisms responsible for the expression of rhythmic behavioral patterns are poorly understood. Here we show that Caenorhabditis elegans switches between distinct forms of locomotion, or crawling versus swimming, when transitioning between solid and liquid environments. These forms of locomotion are distinguished by distinct kinematics and different underlying patterns of neuromuscular activity, as determined by in vivo calcium imaging. The expression of swimming versus crawling rhythms is regulated by sensory input. In a screen for mutants that are defective in transitioning between crawl and swim behavior, we identified unc-79 and unc-80, two mutants known to be defective in NCA ion channel stabilization. Genetic and behavioral analyses suggest that the NCA channels enable the transition to rapid rhythmic behaviors in C. elegans. unc-79, unc-80, and the NCA channels represent a conserved set of genes critical for behavioral pattern generation.neural rhythms ͉ neurogenetics ͉ sodium leak channel D ifferent forms of rhythmic neural output are ubiquitously observed in motor behaviors such as locomotion, respiration, and feeding (1-4). Extensive research has revealed that a neural network can switch among alternate rhythms by altering the properties of specific intrinsic membrane currents and synapses (5). Consistent with this framework, some proteins appear to contribute more to the generation of one rhythm than other rhythms. For instance, channels that carry the persistent sodium current appear to be important for gasping but not the normal respiratory rhythm when studied in vitro (6). Physiological approaches are sometimes limited when trying to identify specific proteins involved in certain rhythms, however, because of the availability and selectivity of compounds that act on the relevant molecules. With the advent of reverse genetics, these limitations are beginning to be overcome by knocking out or modifying specific genes (7, 8), but both pharmacological and gene manipulation approaches are still limited by the a priori hypotheses on which molecules to target. In contrast, because forward genetic studies are unbiased, they can lead to the identification of novel or uncharacterized proteins that contribute to rhythmic neural output. We have therefore pursued a forward genetic approach to identify neural proteins that contribute more to the generation of one form of rhythmic locomotion (i.e., swimming) than another (i.e., crawling) in the nematode Caenorhabditis elegans.C. elegans moves by generating waves of dorsal-ventral (DV) bends along its body. Prior genetic studies have focused on the molecular mechanisms responsible for crawling over a solid agar substrate (9, 10), whereas the motion C. elegans displays in liquid has only begun to be characterized (11). Although C. elegans encounters water in its natural environment (12), it has been unclear whether its motion i...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Screen For Mutants Defective In Transitioning From Cmentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic analysis of crawling and swimming locomotory patterns in C. elegans

Pierce-Shimomura

Chen

Mun

et al. 2008

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

250

265

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“…hpIs61 ) is another active zone marker that expresses the GFPtagged active zone scaffolding protein UNC-10 ( Koushika et al, 2001;Yeh et al, 2008) in the GABAergic motoneurons. In wildtype larvae expressing the hpIs61 marker, GFP::UNC-10 puncta of even size and spacing are present along the dorsal cord ( Fig.…”

Section: Unc-7 Is Specifically Required For Proper Active Zone Differmentioning

confidence: 99%

Caenorhabditis elegansInnexins Regulate Active Zone Differentiation

Yeh

Kawano²,

Ng³

et al. 2009

J. Neurosci.

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In a genetic screen for active zone defective mutants in Caenorhabditis elegans, we isolated a loss-of-function allele of unc-7, a gene encoding an innexin/pannexin family gap junction protein. Innexin UNC-7 regulates the size and distribution of active zones at C. elegans neuromuscular junctions. Loss-of-function mutations in another innexin, UNC-9, cause similar active zone defects as unc-7 mutants. In addition to presumptive gap junction localizations, both UNC-7 and UNC-9 are also localized perisynaptically throughout development and required in presynaptic neurons to regulate active zone differentiation. Our mosaic analyses, electron microscopy, as well as expression studies suggest a novel and likely nonjunctional role of specific innexins in active zone differentiation in addition to gap junction formations.

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Phenotypic evolution of UNC80 loss of function

Valkanas

Schaffer

Dunham

et al. 2016

American J of Med Genetics Pt A

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Failure to thrive arises as a complication of a heterogeneous group of disorders. We describe two female siblings with spastic paraplegia and global developmental delay but also, atypically for the HSPs, poor weight gain classified as failure to thrive. After extensive clinical and biochemical investigations failed to identify the etiology, we used exome sequencing to identify biallelic UNC80 mutations (NM_032504.1:c.[3983-3_3994delinsA];[2431C>T]. The paternally inherited NM_032504.1:c.3983-3_3994delinsA is predicted to encode p.Ser1328Argfs*19 and the maternally inherited NM_032504.1:c.2431C>T is predicted to encode p.Arg811*. No UNC80 mRNA was detectable in patient cultured skin fibroblasts, suggesting UNC80 loss of function by nonsense mediated mRNA decay. Further supporting the UNC80 mutations as causative of these siblings disorder, biallelic mutations in UNC80 have recently been described among individuals with an overlapping phenotype. This report expands the disease spectrum associated with UNC80 mutations.

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A Putative Cation Channel, NCA-1, and a Novel Protein, UNC-80, Transmit Neuronal Activity in C. elegans

Cited by 116 publications

References 45 publications

Genetic analysis of crawling and swimming locomotory patterns in C. elegans

Genetic analysis of crawling and swimming locomotory patterns in C. elegans

Caenorhabditis elegansInnexins Regulate Active Zone Differentiation

Phenotypic evolution of UNC80 loss of function

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