Novel mutations in synaptic transmission genes suppress neuronal hyperexcitation in Caenorhabditis elegans

Katherine A. McCulloch; Yingchuan B. Qi; Seika Takayanagi-Kiya; Yishi Jin; Salvatore J. Cherra

doi:10.1534/g3.117.042598

Novel mutations in synaptic transmission genes suppress neuronal hyperexcitation in Caenorhabditis elegans

Katherine A. McCulloch, Yingchuan B. Qi, Seika Takayanagi-Kiya, Yishi Jin, Salvatore J. Cherra

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Acetylcholine (ACh) receptors (AChR) regulate neural circuit activity in multiple contexts. In humans, mutations in ionotropic acetylcholine receptor (iAChR) genes can cause neurological disorders, including myasthenia gravis and epilepsy. In Caenorhabditis elegans, iAChRs play multiple roles in the locomotor circuit. The cholinergic motor neurons express an ACR-2-containing pentameric AChR (ACR- 2R) comprised of ACR-2, ACR-3, ACR-12, UNC-38, and UNC-63 subunits. A gain-of-function mutation in the non-a subunit gene acr-2 [acr-2(gf)] causes defective locomotion as well as spontaneous convulsions. Previous studies of genetic suppressors of acr-2(gf) have provided insights into ACR-2R composition and assembly. Here, to further understand how the ACR-2R regulates neuronal activity, we expanded the suppressor screen for acr-2(gf)-induced convulsions. The majority of these suppressor mutations affect genes that play critical roles in synaptic transmission, including two novel mutations in the vesicular ACh transporter unc-17. In addition, we identified a role for a conserved major facilitator superfamily domain (MFSD) protein, mfsd-6, in regulating neural circuit activity. We further defined a role for the sphingosine (SPH) kinase (Sphk) sphk-1 in cholinergic neuron activity, independent of previously known signaling pathways. Overall, the genes identified in our study suggest that optimal modulation of synaptic activity is balanced by the differential activities of multiple pathways, and the novel alleles provide valuable reagents to further dissect neuronal mechanisms regulating the locomotor circuit.

Original language	English
Pages (from-to)	2055-2063
Number of pages	9
Journal	G3: Genes, Genomes, Genetics
Volume	7
Issue number	7
DOIs	https://doi.org/10.1534/g3.117.042598
State	Published - Jul 1 2017

Bibliographical note

Funding Information:
We thank Bhavika Anandpura for assistance in mapping the ju815 allele. We thank Derek Sieburth for OJ802 and KP4010 strains and Shohei Mitani at National BioResource Project in Japan for deletion alleles. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). This work was supported in part by NIH institutional training grants (T32 NS007220 to K.A.M. and S.J.C. and T32 AG000216 to K.A.M.), and grants to S.J.C. (F32 NS081945 and K99 NS097638) and Y.J. (R01 NS035546). Y.J. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2017 McCulloch et al.

Keywords

Acetylcholine receptor
Acetylcholine transporter
Epilepsy
Lipid
Locomotion
Major facilitator superfamily domain (MFSD) proteins
Seizure
Sphingosine kinase/sphk-1
Unc-17

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1534/g3.117.042598

Cite this

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title = "Novel mutations in synaptic transmission genes suppress neuronal hyperexcitation in Caenorhabditis elegans",

abstract = "Acetylcholine (ACh) receptors (AChR) regulate neural circuit activity in multiple contexts. In humans, mutations in ionotropic acetylcholine receptor (iAChR) genes can cause neurological disorders, including myasthenia gravis and epilepsy. In Caenorhabditis elegans, iAChRs play multiple roles in the locomotor circuit. The cholinergic motor neurons express an ACR-2-containing pentameric AChR (ACR- 2R) comprised of ACR-2, ACR-3, ACR-12, UNC-38, and UNC-63 subunits. A gain-of-function mutation in the non-a subunit gene acr-2 [acr-2(gf)] causes defective locomotion as well as spontaneous convulsions. Previous studies of genetic suppressors of acr-2(gf) have provided insights into ACR-2R composition and assembly. Here, to further understand how the ACR-2R regulates neuronal activity, we expanded the suppressor screen for acr-2(gf)-induced convulsions. The majority of these suppressor mutations affect genes that play critical roles in synaptic transmission, including two novel mutations in the vesicular ACh transporter unc-17. In addition, we identified a role for a conserved major facilitator superfamily domain (MFSD) protein, mfsd-6, in regulating neural circuit activity. We further defined a role for the sphingosine (SPH) kinase (Sphk) sphk-1 in cholinergic neuron activity, independent of previously known signaling pathways. Overall, the genes identified in our study suggest that optimal modulation of synaptic activity is balanced by the differential activities of multiple pathways, and the novel alleles provide valuable reagents to further dissect neuronal mechanisms regulating the locomotor circuit.",

keywords = "Acetylcholine receptor, Acetylcholine transporter, Epilepsy, Lipid, Locomotion, Major facilitator superfamily domain (MFSD) proteins, Seizure, Sphingosine kinase/sphk-1, Unc-17",

author = "McCulloch, {Katherine A.} and Qi, {Yingchuan B.} and Seika Takayanagi-Kiya and Yishi Jin and Cherra, {Salvatore J.}",

note = "Funding Information: We thank Bhavika Anandpura for assistance in mapping the ju815 allele. We thank Derek Sieburth for OJ802 and KP4010 strains and Shohei Mitani at National BioResource Project in Japan for deletion alleles. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). This work was supported in part by NIH institutional training grants (T32 NS007220 to K.A.M. and S.J.C. and T32 AG000216 to K.A.M.), and grants to S.J.C. (F32 NS081945 and K99 NS097638) and Y.J. (R01 NS035546). Y.J. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2017 McCulloch et al.",

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AU - Qi, Yingchuan B.

AU - Takayanagi-Kiya, Seika

AU - Jin, Yishi

AU - Cherra, Salvatore J.

N1 - Funding Information: We thank Bhavika Anandpura for assistance in mapping the ju815 allele. We thank Derek Sieburth for OJ802 and KP4010 strains and Shohei Mitani at National BioResource Project in Japan for deletion alleles. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). This work was supported in part by NIH institutional training grants (T32 NS007220 to K.A.M. and S.J.C. and T32 AG000216 to K.A.M.), and grants to S.J.C. (F32 NS081945 and K99 NS097638) and Y.J. (R01 NS035546). Y.J. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: © 2017 McCulloch et al.

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N2 - Acetylcholine (ACh) receptors (AChR) regulate neural circuit activity in multiple contexts. In humans, mutations in ionotropic acetylcholine receptor (iAChR) genes can cause neurological disorders, including myasthenia gravis and epilepsy. In Caenorhabditis elegans, iAChRs play multiple roles in the locomotor circuit. The cholinergic motor neurons express an ACR-2-containing pentameric AChR (ACR- 2R) comprised of ACR-2, ACR-3, ACR-12, UNC-38, and UNC-63 subunits. A gain-of-function mutation in the non-a subunit gene acr-2 [acr-2(gf)] causes defective locomotion as well as spontaneous convulsions. Previous studies of genetic suppressors of acr-2(gf) have provided insights into ACR-2R composition and assembly. Here, to further understand how the ACR-2R regulates neuronal activity, we expanded the suppressor screen for acr-2(gf)-induced convulsions. The majority of these suppressor mutations affect genes that play critical roles in synaptic transmission, including two novel mutations in the vesicular ACh transporter unc-17. In addition, we identified a role for a conserved major facilitator superfamily domain (MFSD) protein, mfsd-6, in regulating neural circuit activity. We further defined a role for the sphingosine (SPH) kinase (Sphk) sphk-1 in cholinergic neuron activity, independent of previously known signaling pathways. Overall, the genes identified in our study suggest that optimal modulation of synaptic activity is balanced by the differential activities of multiple pathways, and the novel alleles provide valuable reagents to further dissect neuronal mechanisms regulating the locomotor circuit.

AB - Acetylcholine (ACh) receptors (AChR) regulate neural circuit activity in multiple contexts. In humans, mutations in ionotropic acetylcholine receptor (iAChR) genes can cause neurological disorders, including myasthenia gravis and epilepsy. In Caenorhabditis elegans, iAChRs play multiple roles in the locomotor circuit. The cholinergic motor neurons express an ACR-2-containing pentameric AChR (ACR- 2R) comprised of ACR-2, ACR-3, ACR-12, UNC-38, and UNC-63 subunits. A gain-of-function mutation in the non-a subunit gene acr-2 [acr-2(gf)] causes defective locomotion as well as spontaneous convulsions. Previous studies of genetic suppressors of acr-2(gf) have provided insights into ACR-2R composition and assembly. Here, to further understand how the ACR-2R regulates neuronal activity, we expanded the suppressor screen for acr-2(gf)-induced convulsions. The majority of these suppressor mutations affect genes that play critical roles in synaptic transmission, including two novel mutations in the vesicular ACh transporter unc-17. In addition, we identified a role for a conserved major facilitator superfamily domain (MFSD) protein, mfsd-6, in regulating neural circuit activity. We further defined a role for the sphingosine (SPH) kinase (Sphk) sphk-1 in cholinergic neuron activity, independent of previously known signaling pathways. Overall, the genes identified in our study suggest that optimal modulation of synaptic activity is balanced by the differential activities of multiple pathways, and the novel alleles provide valuable reagents to further dissect neuronal mechanisms regulating the locomotor circuit.

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Novel mutations in synaptic transmission genes suppress neuronal hyperexcitation in Caenorhabditis elegans

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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