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The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor


Various social behaviours in mice are regulated by chemical signals called pheromones that act through the vomeronasal system1,2,3. Exocrine gland-secreting peptide 1 (ESP1) is a 7-kDa peptide that is released into male tear fluids and stimulates vomeronasal sensory neurons in female mice4. Here, we describe the molecular and neural mechanisms that are involved in the decoding of ESP1 signals in the vomeronasal system, which leads to behavioural output in female mice. ESP1 is recognized by a specific vomeronasal receptor, V2Rp5, and the ligand–receptor interaction results in sex-specific signal transmission to the amygdaloid and hypothalamic nuclei via the accessory olfactory bulb. Consequently, ESP1 enhances female sexual receptive behaviour upon male mounting (lordosis), allowing successful copulation. In V2Rp5-deficient mice, ESP1 induces neither neural activation nor sexual behaviour. These findings show that ESP1 is a crucial male pheromone that regulates female reproductive behaviour through a specific receptor in the mouse vomeronasal system.

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Figure 1: V2Rp5 is a functional receptor for ESP1.
Figure 2: ESP1 signal is transmitted to the AOB neurons through the V2Rp5 receptor.
Figure 3: ESP1-induced c-Fos expression in neurons in the higher brain centres.
Figure 4: ESP1-induced sexual receptive behaviour in female mice.

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Primary accessions


Data deposits

The sequences of V2Rp1–V2Rp7 are deposited in GenBank under accession numbers AB540943–AB540949.


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We thank R. Axel, C. R. Yu, M. Cappechi, M. Sugita and T. Shiroishi for mice and plasmids; RIKEN BSI Research Resource Center, Y. Zhang, J. He, C. R. Yu, H. Kimoto, N. Matsumoto, M. Ohmoto, K. Abe, S. Mitsui, T. Kaneko-Goto, and T. Abe for experimental help and advice; and Y. Sakuma, Y. Mori, M. Ichikawa and H. Terasawa for valuable comments and discussions. This work was supported by grants from the Program for Promotion of Basic Research Activities for Innovative Biosciences, Japan Society for the Promotion of Science, and Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information




Experiments were performed by S.H. (Figs 1, 2, 3, 4 and Supplementary Figs 1–14), S.H. and K.S. (Fig. 1e–h) and T.K., T.H. and S.H. (Fig. 4a–d and Supplementary Figs 11–14). S.H. and Y.Y. generated the BAC transgenic mice. T.S. and Y.Y. generated the V2Rp5-deficient mice. R.K. and H.S. advised on the construction of the BAC transgene. K.T. supervised the project. The manuscript was written by S.H., Y.Y. and K.T.

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Correspondence to Kazushige Touhara.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S14 with legends. (PDF 4238 kb)

Supplementary Movie 1

This file contains the control movie. (MOV 5630 kb)

Supplementary Movie 2

This file contains the ESP1 movie. (MOV 7555 kb)

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Haga, S., Hattori, T., Sato, T. et al. The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor. Nature 466, 118–122 (2010).

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