PUBLICATION

Targeted knockout of a chemokine-like gene increases anxiety and fear responses

Authors
Choi, J.H., Jeong, Y.M., Kim, S., Lee, B., Ariyasiri, K., Kim, H.T., Jung, S.H., Hwang, K.S., Choi, T.I., Park, C.O., Huh, W.K., Carl, M., Rosenfeld, J.A., Raskin, S., Ma, A., Gecz, J., Kim, H.G., Kim, J.S., Shin, H.C., Park, D.S., Gerlai, R., Jamieson, B.B., Kim, J.S., Iremonger, K.J., Lee, S.H., Shin, H.S., Kim, C.H.
ID
ZDB-PUB-180118-14
Date
2018
Source
Proceedings of the National Academy of Sciences of the United States of America   115(5): E1041-E1050 (Journal)
Registered Authors
Carl, Matthias, Choi, Jung-Hwa, Gerlai, Robert T., Jung, Seung-Hyun, Kim, Cheol-Hee, Kim, Hyun-Taek
Keywords
anxiety, chemokine-like, fear, knockout, zebrafish
MeSH Terms
  • Animals
  • Anxiety/genetics*
  • Anxiety Disorders
  • Autism Spectrum Disorder/genetics*
  • Behavior, Animal
  • Chemokines/genetics*
  • Conditioning, Psychological/physiology
  • Disease Models, Animal
  • Fear*
  • Female
  • Gene Deletion
  • Genetic Variation
  • Green Fluorescent Proteins/metabolism
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation*
  • RNA, Messenger/metabolism
  • Social Behavior
  • Zebrafish
(all 22)
PubMed
29339520 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, samdori (sam), and present functional characterization of one of its members, sam2 We show exclusive mRNA expression of sam2 in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased crh mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a Sam2 KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of SAM2, and were able to refine a candidate gene region encompassing SAM2, among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of sam2 in regulating mechanisms associated with anxiety.
Genes / Markers
Marker Marker Type Name
agrpGENEagouti related neuropeptide
aoc1GENEamine oxidase copper containing 1
crhbGENEcorticotropin releasing hormone b
cxcr4bGENEchemokine (C-X-C motif), receptor 4b
fevGENEFEV transcription factor, ETS family member
fosabGENEv-fos FBJ murine osteosarcoma viral oncogene homolog Ab
gad1bGENEglutamate decarboxylase 1b
gad2GENEglutamate decarboxylase 2
hcrtGENEhypocretin (orexin) neuropeptide precursor
kctd12.1GENEpotassium channel tetramerisation domain containing 12.1
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Figures
Figure Gallery (9 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
tafa2ck001a/ck001astandard conditionsAdult
tafa2ck001a/ck001astandard conditionsAdult
tafa2ck001a/ck001astressProtruding-mouth
tafa2ck001b/ck001bstandard conditionsAdult
1 - 4 of 4
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ck001a
    		Small Deletion
    ck001b
      		Small Deletion
      hd1TgTransgenic Insertion
        st70TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          No data available
          Fish
          Fish
          hd1Tg
          st70Tg
          tafa2ck001a/ck001a
          tafa2ck001a/ck001a; hd1Tg
          tafa2ck001a/ck001a; st70Tg/st70Tg
          tafa2ck001b/ck001b
          WT
          1 - 7 of 7
          Show
          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          GFPEFGGFP
          1 - 2 of 2
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          Mapping
          No data available
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          Citation
          Choi, J.H., Jeong, Y.M., Kim, S., Lee, B., Ariyasiri, K., Kim, H.T., Jung, S.H., Hwang, K.S., Choi, T.I., Park, C.O., Huh, W.K., Carl, M., Rosenfeld, J.A., Raskin, S., Ma, A., Gecz, J., Kim, H.G., Kim, J.S., Shin, H.C., Park, D.S., Gerlai, R., Jamieson, B.B., Kim, J.S., Iremonger, K.J., Lee, S.H., Shin, H.S., Kim, C.H. (2018) Targeted knockout of a chemokine-like gene increases anxiety and fear responses. Proceedings of the National Academy of Sciences of the United States of America. 115(5):E1041-E1050.