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Molecular Biology of Pheromone Perception in Mammals

Research Summary

Catherine Dulac is investigating the molecular logic of olfactory signaling underlying the coding of odorant- and pheromone-mediated signals and is interested in the developmental processes that ensure appropriate neuronal connections between the olfactory sensory neurons and the brain.

Pheromones have evolved in all animal phyla, including mammals, to signal the sex and the dominance status of animals and to promote mating and social rituals among conspecifics. In mammals, pheromones are primarily detected in a distinct olfactory structure apposed to the ventral nasal septum, the vomeronasal organ (VNO). The ability to associate VNO chemosensory stimulation with specific behavioral arrays and defined hormone changes provides a unique opportunity to uncover the neural basis of mammalian behavior.

Work performed in our lab has been instrumental in identifying novel families of candidate pheromone receptors as well as molecules unique to the VNO that are likely to be associated with pheromone detection. The isolation of the olfactory receptor genes both in mammals and in Caenorhabditis elegans has led to breakthroughs in our understanding of olfactory sensory coding. Similarly, the molecular and functional characterization of VNO-specific receptors and signaling molecules is likely to provide insight into the logic of the pheromone-evoked responses in the mammalian brain.

We have developed a molecular technology to generate and analyze cDNA libraries from individual neurons. The construction of single-cell libraries is invaluable in the nervous system because neurons, even within the same neural structure, display heterogeneous molecular properties and neural connectivity. The ability to investigate specific gene expression in individual cells provides a powerful tool to analyze the molecular basis of neuronal identity. We have used this approach to discover different classes of VNO sensory neurons, to characterize their receptor properties, and to proceed with analysis of olfactory development and function. We are currently using microarray technologies to analyze olfactory development at the single-cell level in the embryonic nose and in the brain.

Our cloning efforts have led to the identification of large and divergent families of candidate pheromone receptors in the VNO. We estimate that the receptor gene families contain as many as 400 putative pheromone receptors subdivided into distinct subgroups. This exceeds previous estimates and suggests that a remarkable molecular and cellular complexity is required for pheromone detection. What is the molecular and functional significance of this organization? We have uncovered a wiring diagram of the VNO fibers within the anterior accessory olfactory bulb (AOB) that appears perfectly suited to accomplish the integration of multiple receptor inputs. This led us to propose a model of pheromone information processing in which the VNO acts as a sensor for a variety of chemical cues and the AOB mitral cells function as coincidence detectors to ensure the pheromone response is specific to the species, the sex, and the individual.

What is the exact role of the VNO in the control of animal behavior? Genetic ablation of the transient receptor potential C2 channel (TRPC2), a candidate signaling molecule in the mouse VNO, allowed us to assess VNO-mediated sensory responses and behaviors directly. We found that TRPC2 deficiency eliminates the sensory activation of VNO neurons by urine pheromones. Moreover, the absence of VNO function has striking behavioral effects. TRPC2–/– male mice appear unable to recognize the sexual identity of their conspecifics: they fail to display the pheromone-evoked aggression toward male intruders that is normally seen in wild-type males and, remarkably, they display courtship and mounting behavior indiscriminately toward both males and females. Our data contradict the established notion that VNO activity is required for the initiation of male-female mating behavior in the mouse and suggest instead a critical role in ensuring sex discrimination.

This leads in turn to the following question: How is a specific gender identified by VNO neurons? In collaboration with the lab of Markus Meister (Harvard University), we have obtained the simultaneous recording of action potentials from large subsets of VNO neurons. This enabled us to demonstrate that subsets of VNO neurons are strongly selective for either male or female pheromones, while other neurons appear to recognize pheromones that vary between individuals of the same sex. The population recording of VNO neurons provides a powerful tool to investigate the complex sensory recognition involved in the pheromone-evoked response: the discrimination of the species, the sex, the familial status, or the individual differences among animals.

At the molecular level, the VNO of the mouse has two neuronal compartments expressing distinct families of pheromone receptors, the V1Rs and the V2Rs. We have recently reported the characterization of two families of major histocompatibility complex (MHC) class Ib molecules, the M10 and the M1 families, that show restricted expression in V2R-expressing neurons. The functional characterization of M10 highlights an unexpected role for MHC molecules in pheromone detection by mammalian VNO neurons and opens new avenues of research on the process of sensory detection leading to behavior.

These projects have been partially supported by an award from the Wellcome Trust and by a grant from the National Institutes of Health.

As of August 16, 2004

Scientist Profile

Investigator
Harvard University
Genetics, Neuroscience