Research Article: Conditional Deletion of ERK5 MAP Kinase in the Nervous System Impairs Pheromone Information Processing and Pheromone-Evoked Behaviors

Date Published: October 9, 2013

Publisher: Public Library of Science

Author(s): Junhui Zou, Daniel R. Storm, Zhengui Xia, Allan Siegel.


ERK5 MAP kinase is highly expressed in the developing nervous system but absent in most regions of the adult brain. It has been implicated in regulating the development of the main olfactory bulb and in odor discrimination. However, whether it plays an essential role in pheromone-based behavior has not been established. Here we report that conditional deletion of the Mapk7 gene which encodes ERK5 in mice in neural stem cells impairs several pheromone-mediated behaviors including aggression and mating in male mice. These deficits were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety, or by depression. Using mouse urine as a natural pheromone-containing solution, we provide evidence that the behavior impairment was associated with defects in the detection of closely related pheromones as well as with changes in their innate preference for pheromones related to sexual and reproductive activities. We conclude that expression of ERK5 during development is critical for pheromone response and associated animal behavior in adult mice.

Partial Text

Vertebrates rely on chemosensory mechanisms to detect food sources, recognize social and mating partners, and avoid predators. It was originally thought that pheromones are primarily sensed through the vomeronasal organ (VNO) while odorants are detected through the main olfactory epithelium (MOE) [1–5]. Chemical signals acquired through the MOE and VNO are processed and integrated in the main olfactory bulb (MOB) and the accessory olfactory bulb (AOB), respectively. Detection of volatile odorants by the MOE is associated with several behaviors including food detection, whereas the detection of pheromones by the accessory olfactory system mediates several types of complex behavior including social and sexual activities. However, more recent studies have suggested that the MOE also plays a critical role in the detection of pheromones and the execution of gender-specific behavior such as male aggression and mating [6–9]. For example, male mice lacking functional CNGA2 (cyclic nucleotide-gated channel alpha 2) or AC3 (type-3 adenylyl cyclase), proteins that are required for the signal transduction through the MOE but are not expressed in the VNO, do not exhibit male dominance and male sexual activity [10,11]. Thus, both the MOE/MOB and VNO/AOB systems participate in pheromone detection and associated behaviors.

Although the ERK5 MAP kinase is highly expressed in the developing nervous system [17,18], several studies reported that it is dispensable for the development of the brain [29,30]. We also observed that conditional deletion of ERK5 in neural stem cells does not cause gross abnormalities of the brain [19]. However, we recently reported that the MOB of ERK5 cKO mice is smaller due to reduced number of GABAergic interneurons generated during development [19]. ERK5 cKO mice are also deficient in odor discrimination between structurally similar odorants. We report here that ERK5 cKO mice also have smaller AOB. The objective of this study was to investigate whether the smaller MOB and AOB in ERK5 cKO mice lead to changes in pheromone-mediated behaviors.