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A conserved function of C. elegans CASY-1 calsyntenin in associative learning.

Hoerndli FJ, Walser M, Fröhli Hoier E, de Quervain D, Papassotiropoulos A, Hajnal A - PLoS ONE (2009)

Bottom Line: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance.However, such studies do not allow for a functional or causal testing of newly identified candidate genes.Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Zoology, University of Zürich, Zürich, Switzerland.

ABSTRACT

Background: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance. However, such studies do not allow for a functional or causal testing of newly identified candidate genes. Since polymorphisms in Calsyntenin 2 (CLSTN2) showed a significant association with episodic memory performance in humans, we tested the C. elegans CLSTN2 ortholog CASY-1 for possible functions in the associative behavior of C. elegans.

Methodology/principal findings: Using three different associative learning paradigms and functional rescue experiments, we show that CASY-1 plays an important role during associative learning in C. elegans. Furthermore, neuronal expression of human CLSTN2 in C. elegans rescues the learning defects of casy-1 mutants. Finally, genetic interaction studies and neuron-specific expression experiments suggest that CASY-1 may regulate AMPA-like GLR-1 glutamate receptor signaling.

Conclusion/significance: Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway.

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Expression pattern of a transcriptional casy-1 reporter.(A) Expression of the casy-1p::RFP transcriptional reporter (red) and (B) a GLR-1::GFP translational reporter (blue) [22] in the nerve ring of an adult animal. A 3D reconstruction of confocal sections through the left hemisphere is shown (see methods). The two arrowheads in the bottom right corner point at RMDDL and SMDDL and the arrowhead in the top half points at SMDVL, which co-express casy-1p::RFP and GLR-1::GFP. Anterior is left and ventral is bottom. Scale bar in (B) is 10 µm.
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pone-0004880-g002: Expression pattern of a transcriptional casy-1 reporter.(A) Expression of the casy-1p::RFP transcriptional reporter (red) and (B) a GLR-1::GFP translational reporter (blue) [22] in the nerve ring of an adult animal. A 3D reconstruction of confocal sections through the left hemisphere is shown (see methods). The two arrowheads in the bottom right corner point at RMDDL and SMDDL and the arrowhead in the top half points at SMDVL, which co-express casy-1p::RFP and GLR-1::GFP. Anterior is left and ventral is bottom. Scale bar in (B) is 10 µm.

Mentions: CLSTN2 is a type I transmembrane protein with two extracellular calcium-binding cadherin domains and two intracellular kinesin light chain-binding domains [15], [16]. These domains are conserved in all three Calsyntenin family members including C. elegans CASY-1 [15]. Similar to mammalian Calsyntenins, a transcriptional casy-1 reporter is expressed in many head nerve ring neurons, some of which send processes into the ventral nerve cord (Fig. 2A and data not shown). Moreover, a GFP-tagged CASY-1 protein was reported to localize at synapses (Duan and Hedgecock, personal communication). Given the sequence similarity between human CLSTN2 and C. elegans CASY-1 and their neuronal expression in both organisms, we asked whether the casy-1 gene might function in regulating associative learning in C. elegans. The casy-1 deletion mutant tm718 (kindly provided by S. Mitani) contains a 601 bp deletion in exon 4, creating a frameshift followed by a premature stop codon. The tm718 allele results in the production of a protein truncated at position 117 that lacks most of the extracellular and the entire intracellular domain. We observed no obvious anatomical, behavioral or locomotory defects in naive casy-1(tm718) animals (Fig. 1B,C). Moreover, casy-1(tm718) animals appear healthy and are fertile.


A conserved function of C. elegans CASY-1 calsyntenin in associative learning.

Hoerndli FJ, Walser M, Fröhli Hoier E, de Quervain D, Papassotiropoulos A, Hajnal A - PLoS ONE (2009)

Expression pattern of a transcriptional casy-1 reporter.(A) Expression of the casy-1p::RFP transcriptional reporter (red) and (B) a GLR-1::GFP translational reporter (blue) [22] in the nerve ring of an adult animal. A 3D reconstruction of confocal sections through the left hemisphere is shown (see methods). The two arrowheads in the bottom right corner point at RMDDL and SMDDL and the arrowhead in the top half points at SMDVL, which co-express casy-1p::RFP and GLR-1::GFP. Anterior is left and ventral is bottom. Scale bar in (B) is 10 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654071&req=5

pone-0004880-g002: Expression pattern of a transcriptional casy-1 reporter.(A) Expression of the casy-1p::RFP transcriptional reporter (red) and (B) a GLR-1::GFP translational reporter (blue) [22] in the nerve ring of an adult animal. A 3D reconstruction of confocal sections through the left hemisphere is shown (see methods). The two arrowheads in the bottom right corner point at RMDDL and SMDDL and the arrowhead in the top half points at SMDVL, which co-express casy-1p::RFP and GLR-1::GFP. Anterior is left and ventral is bottom. Scale bar in (B) is 10 µm.
Mentions: CLSTN2 is a type I transmembrane protein with two extracellular calcium-binding cadherin domains and two intracellular kinesin light chain-binding domains [15], [16]. These domains are conserved in all three Calsyntenin family members including C. elegans CASY-1 [15]. Similar to mammalian Calsyntenins, a transcriptional casy-1 reporter is expressed in many head nerve ring neurons, some of which send processes into the ventral nerve cord (Fig. 2A and data not shown). Moreover, a GFP-tagged CASY-1 protein was reported to localize at synapses (Duan and Hedgecock, personal communication). Given the sequence similarity between human CLSTN2 and C. elegans CASY-1 and their neuronal expression in both organisms, we asked whether the casy-1 gene might function in regulating associative learning in C. elegans. The casy-1 deletion mutant tm718 (kindly provided by S. Mitani) contains a 601 bp deletion in exon 4, creating a frameshift followed by a premature stop codon. The tm718 allele results in the production of a protein truncated at position 117 that lacks most of the extracellular and the entire intracellular domain. We observed no obvious anatomical, behavioral or locomotory defects in naive casy-1(tm718) animals (Fig. 1B,C). Moreover, casy-1(tm718) animals appear healthy and are fertile.

Bottom Line: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance.However, such studies do not allow for a functional or causal testing of newly identified candidate genes.Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Zoology, University of Zürich, Zürich, Switzerland.

ABSTRACT

Background: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance. However, such studies do not allow for a functional or causal testing of newly identified candidate genes. Since polymorphisms in Calsyntenin 2 (CLSTN2) showed a significant association with episodic memory performance in humans, we tested the C. elegans CLSTN2 ortholog CASY-1 for possible functions in the associative behavior of C. elegans.

Methodology/principal findings: Using three different associative learning paradigms and functional rescue experiments, we show that CASY-1 plays an important role during associative learning in C. elegans. Furthermore, neuronal expression of human CLSTN2 in C. elegans rescues the learning defects of casy-1 mutants. Finally, genetic interaction studies and neuron-specific expression experiments suggest that CASY-1 may regulate AMPA-like GLR-1 glutamate receptor signaling.

Conclusion/significance: Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway.

Show MeSH
Related in: MedlinePlus