@article{420e31530a764461ab9c42c4e60c741e,
title = "Targeted knockout of a chemokine-like gene increases anxiety and fear responses",
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.",
keywords = "Chemokine-like, anxiety, fear, knockout, zebrafish",
author = "Choi, {Jung Hwa} and Jeong, {Yun Mi} and Sujin Kim and Boyoung Lee and Krishan Ariyasiri and Kim, {Hyun Taek} and Jung, {Seung Hyun} and Hwang, {Kyu Seok} and Choi, {Tae Ik} and Park, {Chul O.} and Huh, {Won Ki} and Matthias Carl and Rosenfeld, {Jill A.} and Salmo Raskin and Alan Ma and Jozef Gecz and Kim, {Hyung Goo} and Kim, {Jin Soo} and Shin, {Ho Chul} and Park, {Doo Sang} and Robert Gerlai and Jamieson, {Bradley B.} and Kim, {Joon S.} and Iremonger, {Karl J.} and Lee, {Sang H.} and Shin, {Hee Sup} and Kim, {Cheol Hee}",
note = "Funding Information: We thank Ted Inpyo Hong, Soojin Ryu, and Cecilia Hillard for proofreading and critical review of the manuscript. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. This work was supported by Ministry of Trade, Industry and Energy, Korea Grant 10063396; the National Research Foundation of Korea Grants 2017R1A2B2010696 and 2017M3A9A5051180; Institute for Basic Science Grants IBS-R001-D1 and IBS-R021; and a Natural Sciences and Engineering Research Council grant (to R.G.). Funding Information: ACKNOWLEDGMENTS. We thank Ted Inpyo Hong, Soojin Ryu, and Cecilia Hillard for proofreading and critical review of the manuscript. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. This work was supported by Ministry of Trade, Industry and Energy, Korea Grant 10063396; the National Research Foundation of Korea Grants 2017R1A2B2010696 and 2017M3A9A5051180; Institute for Basic Science Grants IBS-R001-D1 and IBS-R021; and a Natural Sciences and Engineering Research Council grant (to R.G.).",
year = "2018",
month = jan,
day = "30",
doi = "10.1073/pnas.1707663115",
language = "English (US)",
volume = "115",
pages = "E1041--E1050",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "5",
}