Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors

Yibing Wang; Liqin Cao; Chia Ying Lee; Tomohiko Matsuo; Kejia Wu; Greg Asher; Lijun Tang; Tsuyoshi Saitoh; Jamie L Russell; Daniela Klewe-Nebenius; Li Wang; Shingo Soya; Emi Hasegawa; Yoan Chérasse; Jiamin Zhou; Yuwenbin Li; Tao Wang; Xiaowei Zhan; Chika Miyoshi; Yoko Irukayama; Jie Cao; Julian Meeks; Laurent Gautron; Zhiqiang Wang; Katsuyasu Sakurai; Hiromasa Funato; Takeshi Sakurai; Masashi Yanagisawa; Hiroshi Nagase; Reiko Kobayakawa; Ko Kobayakawa; Bruce A Beutler; Qinghua Liu

doi:10.1038/s41467-018-04324-3

Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors

Yibing Wang, Liqin Cao, Chia Ying Lee, Tomohiko Matsuo, Kejia Wu, Greg Asher, Lijun Tang, Tsuyoshi Saitoh, Jamie L Russell, Daniela Klewe-Nebenius, Li Wang, Shingo Soya, Emi Hasegawa, Yoan Chérasse, Jiamin Zhou, Yuwenbin Li, Tao Wang, Xiaowei Zhan, Chika Miyoshi, Yoko IrukayamaJie Cao, Julian Meeks, Laurent Gautron, Zhiqiang Wang, Katsuyasu Sakurai, Hiromasa Funato, Takeshi Sakurai, Masashi Yanagisawa, Hiroshi Nagase, Reiko Kobayakawa, Ko Kobayakawa, Bruce A Beutler, Qinghua Liu

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

9 Scopus citations

Abstract

Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 ^-/- mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.

Original language	English (US)
Article number	2041
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04324-3
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Wang, Y., Cao, L., Lee, C. Y., Matsuo, T., Wu, K., Asher, G., Tang, L., Saitoh, T., Russell, J. L., Klewe-Nebenius, D., Wang, L., Soya, S., Hasegawa, E., Chérasse, Y., Zhou, J., Li, Y., Wang, T., Zhan, X., Miyoshi, C., ... Liu, Q. (2018). Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors. Nature communications, 9(1), [2041]. https://doi.org/10.1038/s41467-018-04324-3

Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors. / Wang, Yibing; Cao, Liqin; Lee, Chia Ying; Matsuo, Tomohiko; Wu, Kejia; Asher, Greg; Tang, Lijun; Saitoh, Tsuyoshi; Russell, Jamie L; Klewe-Nebenius, Daniela; Wang, Li; Soya, Shingo; Hasegawa, Emi; Chérasse, Yoan; Zhou, Jiamin; Li, Yuwenbin; Wang, Tao ; Zhan, Xiaowei; Miyoshi, Chika; Irukayama, Yoko; Cao, Jie; Meeks, Julian; Gautron, Laurent; Wang, Zhiqiang; Sakurai, Katsuyasu; Funato, Hiromasa; Sakurai, Takeshi; Yanagisawa, Masashi; Nagase, Hiroshi; Kobayakawa, Reiko; Kobayakawa, Ko; Beutler, Bruce A; Liu, Qinghua.

In: Nature communications, Vol. 9, No. 1, 2041, 01.12.2018.

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

Wang, Y, Cao, L, Lee, CY, Matsuo, T, Wu, K, Asher, G, Tang, L, Saitoh, T, Russell, JL, Klewe-Nebenius, D, Wang, L, Soya, S, Hasegawa, E, Chérasse, Y, Zhou, J, Li, Y, Wang, T , Zhan, X, Miyoshi, C, Irukayama, Y, Cao, J, Meeks, J, Gautron, L, Wang, Z, Sakurai, K, Funato, H, Sakurai, T, Yanagisawa, M, Nagase, H, Kobayakawa, R, Kobayakawa, K, Beutler, BA & Liu, Q 2018, 'Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors', Nature communications, vol. 9, no. 1, 2041. https://doi.org/10.1038/s41467-018-04324-3

Wang, Yibing ; Cao, Liqin ; Lee, Chia Ying ; Matsuo, Tomohiko ; Wu, Kejia ; Asher, Greg ; Tang, Lijun ; Saitoh, Tsuyoshi ; Russell, Jamie L ; Klewe-Nebenius, Daniela ; Wang, Li ; Soya, Shingo ; Hasegawa, Emi ; Chérasse, Yoan ; Zhou, Jiamin ; Li, Yuwenbin ; Wang, Tao ; Zhan, Xiaowei ; Miyoshi, Chika ; Irukayama, Yoko ; Cao, Jie ; Meeks, Julian ; Gautron, Laurent ; Wang, Zhiqiang ; Sakurai, Katsuyasu ; Funato, Hiromasa ; Sakurai, Takeshi ; Yanagisawa, Masashi ; Nagase, Hiroshi ; Kobayakawa, Reiko ; Kobayakawa, Ko ; Beutler, Bruce A ; Liu, Qinghua. / Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors. In: Nature communications. 2018 ; Vol. 9, No. 1.

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title = "Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors",

abstract = "Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 -/- mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.",

author = "Yibing Wang and Liqin Cao and Lee, {Chia Ying} and Tomohiko Matsuo and Kejia Wu and Greg Asher and Lijun Tang and Tsuyoshi Saitoh and Russell, {Jamie L} and Daniela Klewe-Nebenius and Li Wang and Shingo Soya and Emi Hasegawa and Yoan Ch{\'e}rasse and Jiamin Zhou and Yuwenbin Li and Tao Wang and Xiaowei Zhan and Chika Miyoshi and Yoko Irukayama and Jie Cao and Julian Meeks and Laurent Gautron and Zhiqiang Wang and Katsuyasu Sakurai and Hiromasa Funato and Takeshi Sakurai and Masashi Yanagisawa and Hiroshi Nagase and Reiko Kobayakawa and Ko Kobayakawa and Beutler, {Bruce A} and Qinghua Liu",

note = "Funding Information: We thank Drs. Y. Mori, R. Sakaguchi, M. Ding, T. Han, and J. Chen for sharing plasmids, Dr. Bart Carter for providing snake skin molts, and Drs. J. Cohen, H. Hu, and Y. Liu for comments on our manuscript. We acknowledge R. Potts, Y. Ogawa, W. Wang, T. Liang, H. Kim, and S. Kim for technical assistance. Q.L. is a W.A. “Tex” Moncrief Jr. Scholar in Biomedical Research. This work was supported by the National Institute of Health (GM111367 to Q.L.; R37GM067759 to B.B.), the Welch Foundation (I-1608 to Q.L.) and UT Southwestern Medical Center (High Impact/High Risk grant to Q.L.) as well as the Japan Society for the Promotion of Science (15K14874 and “Willdynamics” 17H06048 to Q.L.; 26220207 to M.Y., H.M.; 16H02591 to K.K.; 17K08133 to L.C.), the Japan Science and Technology Agency-step grant (AS271516U to K.K., R.K.), and the World Premier International Research Center Initiative (WPI) from MEXT, Japan.",

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doi = "10.1038/s41467-018-04324-3",

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T1 - Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors

AU - Wang, Yibing

AU - Cao, Liqin

AU - Lee, Chia Ying

AU - Matsuo, Tomohiko

AU - Wu, Kejia

AU - Asher, Greg

AU - Tang, Lijun

AU - Saitoh, Tsuyoshi

AU - Russell, Jamie L

AU - Klewe-Nebenius, Daniela

AU - Wang, Li

AU - Soya, Shingo

AU - Hasegawa, Emi

AU - Chérasse, Yoan

AU - Zhou, Jiamin

AU - Li, Yuwenbin

AU - Wang, Tao

AU - Zhan, Xiaowei

AU - Miyoshi, Chika

AU - Irukayama, Yoko

AU - Cao, Jie

AU - Meeks, Julian

AU - Gautron, Laurent

AU - Wang, Zhiqiang

AU - Sakurai, Katsuyasu

AU - Funato, Hiromasa

AU - Sakurai, Takeshi

AU - Yanagisawa, Masashi

AU - Nagase, Hiroshi

AU - Kobayakawa, Reiko

AU - Kobayakawa, Ko

AU - Beutler, Bruce A

AU - Liu, Qinghua

N1 - Funding Information: We thank Drs. Y. Mori, R. Sakaguchi, M. Ding, T. Han, and J. Chen for sharing plasmids, Dr. Bart Carter for providing snake skin molts, and Drs. J. Cohen, H. Hu, and Y. Liu for comments on our manuscript. We acknowledge R. Potts, Y. Ogawa, W. Wang, T. Liang, H. Kim, and S. Kim for technical assistance. Q.L. is a W.A. “Tex” Moncrief Jr. Scholar in Biomedical Research. This work was supported by the National Institute of Health (GM111367 to Q.L.; R37GM067759 to B.B.), the Welch Foundation (I-1608 to Q.L.) and UT Southwestern Medical Center (High Impact/High Risk grant to Q.L.) as well as the Japan Society for the Promotion of Science (15K14874 and “Willdynamics” 17H06048 to Q.L.; 26220207 to M.Y., H.M.; 16H02591 to K.K.; 17K08133 to L.C.), the Japan Science and Technology Agency-step grant (AS271516U to K.K., R.K.), and the World Premier International Research Center Initiative (WPI) from MEXT, Japan.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 -/- mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.

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