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

Abstract

Various social behaviours in mice are regulated by chemical signals called pheromones that act through the vomeronasal system. 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 mice. 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.

From sexual attraction to maternal aggression: When pheromones change their behavioural significance

“…In this respect, it is interesting to note that, although ESP1 is exclusively produced by the lacrimal gland, the harderian, lacrimal and submaxillary glands produce other peptides of the ESP family that are not expressed in a sexually dimorphic way. At least some of these peptides apparently activate VNO cells (Haga et al, 2010), thus suggesting a role of the ESP peptides in social signalling. For instance, it has recently been described that ESP22 is secreted by lacrimal glands of both male and female mice, in a 50-fold higher concentration in juvenile than adults (Ferrero et al, 2013).…”

“…When detected by vomeronasal organ, ESP1 stimulates lordosis in females (Haga et al, 2010), whereas some MUPs have been shown to elicit aggression and countermarking in males (Chamero et al, 2007;Kaur et al, 2014) and attraction in females (Roberts et al, 2010). In addition, type I MHC peptides, showing low volatility, may also act as chemosignals that allow mate recognition in the context of the induction of pregnancy failure (Bruce effect; Leinders-Zufall et al, 2004).…”

“…The lacrimal gland of pubertal and adult male mice (from 4 weeks of age) secretes a 7kD peptide known as ESP1 (Exocrine Secreted Peptide 1), which specifically stimulates VNO cells expressing V2Rp5 vomeronasal receptor (Kimoto et al, 2005;Haga et al, 2010). These vomeronasal cells co-express non-classical class I major histocompatibility genes, also called H2-Mv genes, which apparently contribute to their ultrasensitivity to ESP1 (Leinders-Zufall et al, 2014).…”

“…For instance, BALB/c male mice show very low (virtually undetectable) levels of darcin in their urine (Roberts et al, 2010), whereas ESP1 is absent in the lacrimal fluid of the males of most of the lab strains with the exception of BALB/c and DBA (Haga et al, 2010). This important inter-strain heterogeneity might also affect the composition of the excreted/secreted volatiles.…”

The search for human pheromones: the lost decades and the necessity of returning to first principles

“…Pheromones can be short or long range, or act on contact. In house mice, volatile pheromone molecules detected at a distance of centimetres include dehydro-exobrevicomin and 2-sec-butyl-4,5-dihydrothiazole, whereas the non-volatile male peptide pheromone ESP1 (exocrine glandsecreting peptide 1) gets transferred from the male's tear glands to the nose (and thus vomeronasal organ, VNO) of the female during courtship contact [12].…”