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

Jung Hwa Choi, Yun Mi Jeong, Sujin Kim, Boyoung Lee, Krishan Ariyasiri, Hyun Taek Kim, Seung Hyun Jung, Kyu Seok Hwang, Tae Ik Choi, Chul O. Park, Won Ki Huh, Matthias Carl, Jill A. Rosenfeld, Salmo Raskin, Alan Ma, Jozef Gecz, Hyung Goo Kim, Jin Soo Kim, Ho Chul Shin, Doo Sang Park & 7 others Robert Gerlai, Bradley B. Jamieson, Joon S. Kim, Karl J. Iremonger, Sang H. Lee, Hee Sup Shin, Cheol Hee Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E1041-E1050
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number5
DOIs
StatePublished - Jan 30 2018

Fingerprint

Chemokines
Fear
Zebrafish
Anxiety
Knockout Mice
Genes
Hypothalamus
Habenula
Telencephalon
Messenger RNA
Paraventricular Hypothalamic Nucleus
Anxiety Disorders
Baths
Intellectual Disability
Mammals
Fishes
Animal Models
Neurons
Proteins

Keywords

  • Chemokine-like
  • anxiety
  • fear
  • knockout
  • zebrafish

ASJC Scopus subject areas

  • General

Cite this

Targeted knockout of a chemokine-like gene increases anxiety and fear responses. / Choi, Jung Hwa; Jeong, Yun Mi; Kim, Sujin; Lee, Boyoung; Ariyasiri, Krishan; Kim, Hyun Taek; Jung, Seung Hyun; Hwang, Kyu Seok; Choi, Tae Ik; Park, Chul O.; Huh, Won Ki; Carl, Matthias; Rosenfeld, Jill A.; Raskin, Salmo; Ma, Alan; Gecz, Jozef; Kim, Hyung Goo; Kim, Jin Soo; Shin, Ho Chul; Park, Doo Sang; Gerlai, Robert; Jamieson, Bradley B.; Kim, Joon S.; Iremonger, Karl J.; Lee, Sang H.; Shin, Hee Sup; Kim, Cheol Hee.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 5, 30.01.2018, p. E1041-E1050.

Research output: Contribution to journalArticle

Choi, JH, Jeong, YM, Kim, S, Lee, B, Ariyasiri, K, Kim, HT, Jung, SH, Hwang, KS, Choi, TI, Park, CO, Huh, WK, Carl, M, Rosenfeld, JA, Raskin, S, Ma, A, Gecz, J, Kim, HG, Kim, JS, Shin, HC, Park, DS, Gerlai, R, Jamieson, BB, Kim, JS, Iremonger, KJ, Lee, SH, Shin, HS & Kim, CH 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, vol. 115, no. 5, pp. E1041-E1050. https://doi.org/10.1073/pnas.1707663115
Choi, Jung Hwa ; Jeong, Yun Mi ; Kim, Sujin ; Lee, Boyoung ; Ariyasiri, Krishan ; Kim, Hyun Taek ; Jung, Seung Hyun ; Hwang, Kyu Seok ; Choi, Tae Ik ; Park, Chul O. ; Huh, Won Ki ; Carl, Matthias ; Rosenfeld, Jill A. ; Raskin, Salmo ; Ma, Alan ; Gecz, Jozef ; Kim, Hyung Goo ; Kim, Jin Soo ; Shin, Ho Chul ; Park, Doo Sang ; Gerlai, Robert ; Jamieson, Bradley B. ; Kim, Joon S. ; Iremonger, Karl J. ; Lee, Sang H. ; Shin, Hee Sup ; Kim, Cheol Hee. / Targeted knockout of a chemokine-like gene increases anxiety and fear responses. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 5. pp. E1041-E1050.
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AU - Choi, Jung Hwa

AU - Jeong, Yun Mi

AU - Kim, Sujin

AU - Lee, Boyoung

AU - Ariyasiri, Krishan

AU - Kim, Hyun Taek

AU - Jung, Seung Hyun

AU - Hwang, Kyu Seok

AU - Choi, Tae Ik

AU - Park, Chul O.

AU - Huh, Won Ki

AU - Carl, Matthias

AU - Rosenfeld, Jill A.

AU - Raskin, Salmo

AU - Ma, Alan

AU - Gecz, Jozef

AU - Kim, Hyung Goo

AU - Kim, Jin Soo

AU - Shin, Ho Chul

AU - Park, Doo Sang

AU - Gerlai, Robert

AU - Jamieson, Bradley B.

AU - Kim, Joon S.

AU - Iremonger, Karl J.

AU - Lee, Sang H.

AU - Shin, Hee Sup

AU - Kim, Cheol Hee

PY - 2018/1/30

Y1 - 2018/1/30

N2 - 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.

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