The discovery of a peptide that is secreted from the eyes of male mice and elicits neuronal activity in the vomeronasal organ (VNO) of females, points to a new mode of chemical communication between mammals, according to the authors of a new study in
Kazushige Touhara, who led the study at the University of Tokyo's Department of Integrated Biosciences, said that exocrine gland-secreting peptide (ESP) 1 is "the first non-volatile pheromone" to be identified in mammals and "the first authentic pheromone" found to stimulate the VNO of mice in vivo.
"One of the biggest mysteries in chemosensory perception is that we still haven't figured out what the active pheromone compounds are that mammals use," said Catherine Dulac, Howard Hughes Medical Institute investigator at Harvard University, who was not involved in the study. "In that context, the paper here is extremely important."
To investigate the source of this activation, Touhara's team used c-fos expression as a marker for VNO sensory neuronal activity in mice exposed to various candidate stimuli. While male urine-derived molecules had little or no effect, direct contact with adult males or their shaved fur induced a robust response in females, but not in males. From here, the source was narrowed down to a non-volatile peptide in secretions from the extraorbital lachrimal gland (ELG), which the researchers named ESP1.
In situ hybridization located the ESP1 receptors on a subset of neurons in the V2R region of the female VNO, and electrophysiology techniques confirmed that ESP1-induced c-fos activity was associated with neuronal firing.
The gene encoding the peptide belongs to a previously unrecognised family of 24 genes, of which 10 were expressed by the ELG. Touhara said he now has evidence that other ESP-family peptides also elicit an electrical response in the VNO. And one, he added, is female-specific. "We are characterizing it now, and will report it in the near future."
"This is a beautiful story overall," said Frank Zufall, at the University of Maryland's School of Medicine. All that it lacks, he suggested, are behavioral data. "To call them pheromones, you need to show a behavioral response."
"I don't know why they haven't done that," agreed Dulac. "They could just have put those compounds on the fur of a mouse to see what happens." Touhara said that behavioral studies are in progress. "We know that female mice receiving the peptide behave differently, but we have not gotten a conclusive result yet," he explained. "It is not as simple as people imagine, because this is non-volatile and other signals must also be involved in the final behaviour."
Behavioral work is also needed to shed light on the function of the ESP signal, said Zufall, who was not involved in the study. The VNO might, he said, detect a cocktail of ESP molecules, in which case the chemicals could communicate more than just gender identity.
Zufall, Dulac and Touhara are all intrigued by the location of the ESP-family genes on chromosome 17, adjacent to the major histocompatibility complex (MHC), which itself is the source of molecules that variously signal individual identity and interact with V2R receptors. However, admitted Dulac, "we don't really understand the significance of this."
It also remains to be seen whether contact-mediated chemical signalling is a widespread mode of mammalian communication. The social behavior of mammals – including humans – suggests there are plenty of opportunities for non-volatile signals to be transferred, Zufall told