Research:
Our group is exploring 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. We have developed a molecular technology to generate and analyze cDNA libraries from individual neurons (Dulac and Axel 1995). 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 (Tietjen et al., 2003). We are currently pursuing the analysis of olfactory development at the single cell level using microarray technologies both in the embryonic nose and in the brain. In the VNO, our cloning efforts have led to the identification of large and divergent families of candidate pheromone receptors in the VNO (Dulac and Axel 1995; Herrada and Dulac 1997; Pantages and Dulac 2000). 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 (Belluscio et al. 1999). What is the exact role of the VNO in the control of animal behavior? Genetic ablation of the TRPC2 channel, a candidate signaling molecule in the mouse VNO (Liman et al. 1999; Stowers et al. 2002), demonstrated that TRPC2 deficiency eliminates the sensory activation of VNO neurons by urine pheromones. Moreover, 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 (Stowers et al. 2002). 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. In collaboration with the lab of Markus Meister in the MCB Department, we have obtained the simultaneous recording of action potentials from large subsets of VNO neurons (Holy et. al 2000). 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. At the molecular level, the vomeronasal organ (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 (Loconto et al., 2003). 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. In order to gain insight into sensory processing modulating reproductive behavioral and endocrine changes, we have recently aimed at identifying afferent pathways to neurons synthesizing luteinizing hormone releasing hormone (LHRH), a key neuro-hormone of reproduction (Yoon et al., 2005). Injection of conditional pseudorabies virus into the brain of an LHRH::Cre mouse line led to the identification of neuronal networks connected to LHRH neurons. Remarkably, and in contrast to established notions on the nature of LHRH neuronal inputs, our data identify major olfactory projection pathways originating from a discrete population of olfactory sensory neurons, but fail to document any synaptic connectivity with the vomeronasal system. Accordingly, chemosensory modulation of LHRH neuronal activity and mating behavior are dramatically impaired in absence of olfactory function, while they appear unaffected in mouse mutants lacking vomeronasal signaling. Further visualization of afferents to LHRH neurons across the brain offers a unique opportunity to uncover complex polysynaptic circuits modulating reproduction and fertility.
Selected Publications: Choi, P., Zakhary, L., Choi, W., Alvarez-Saavedra, E., Miska, E., Zhang, J., McManus, M., Harfe, B., Giraldez, A., Horvitz, R.H., Schier, A. and Dulac, C. (2008) Members of the miRNA-200 Family Mediate Olfactory Neurogenesis. Neuron 57:41–55 Kimchi, T., Xu, J. and Dulac, C. (2007) A functional circuit underlying male sexual behaviour in the female mouse brain. Nature 448:1009-1014. Wagner S, Gresser AL, Torello AT, Dulac C. (2006) A Multireceptor Genetic Approach Uncovers an Ordered Integration of VNO Sensory Inputs in the Accessory Olfactory Bulb. Neuron 50: 697-709. Yoon H, L. W. Enquist and Dulac C. (2005) Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell, 123, 669-682. Dulac, C. (2005) Molecular Architecture Of Pheromone Sensing in Mammals. Molecular Mechanisms Influencing Aggressive Behaviours, Novartis Foundation Symposium 268, 100-110. Olson R., Huey-Tubman K.E., Dulac C., Bjorkman P.J. (2005) Structure of a pheromone receptor-associated MHC molecule with an open and empty groove. PLoS Biol 3(8): e257. Tietjen, I., Rihel, J., and Dulac, C. (2005) Single-cell transcriptional profiles and spatial patterning of the mammalian olfactory epithelium. Int. J. Dev. Biol. 49: 201-207 Dulac, C. (2005), Sex and the Single Splice, Cell. 121, 664-666. Dulac, C. and Zakhary, L. (2004). Stem Cells of the Olfactory Epithelium. Handbook of Stem Cells, v2, 233-244. Dulac, C. and Grothe, B. (2004) Editorial: Sensory systems. Current Opinion in Neurobiology, 14, 403-406 Cloutier, J-F., Sahay A., Chang, E.C., Tessier-Lavigne, M., Dulac, C., Kolodkin, A.L., Ginty, D.D. (2004). Differential requirements for Sema3F and Slit-1 in axonal targeting, fasciculation and segregation of olfactory receptor sensory neurons. Journal of Neuroscience 24 (41): 9087–9096. Dulac, C. and Torello, A. T. (2003). Molecular detection of pheromone signals in mammals: from genes to behaviour. Nature Reviews Neuroscience 4: 1-13. Tietjen, I., Rihel, J., Cao, Y., Zachary, L. and Dulac, C., (2003). Single-cell transcriptional analysis of neuronal progenitors. Neuron 38: 161-175. Loconto, J., Papes, F., Chang, E., Stowers, L., Jones, E., Takada, T., Kumanovics, A., Fisher-Lindahl, K., and Dulac, C., (2002). Functional Expression of Murine V2R Pheromone Receptors Involves Selective Association with the M10 and M1 Families of MHC Class Ib Molecules. Cell 2003 112: 607-618. Shumyatsky, G.P., Tsvetkov, E., Malleret, G., Vronskaya, S., Hattton, M., Hampton, L, Battey, J., Dulac, C., Kandel, E. and Bolshakov, V., (2002). Identification of a signaling network in lateral nucleus of amygdala important ofr inhibiting memory specifically related to learned fear. Cell, 111, 905-918. Cloutier, J-F., Giger, R., Koentges, G., Dulac, C., Kolodkin, A. and Ginty, D. (2002). Neuropilin-2 mediates axonal fasciculation, zonal segregation, but not axonal convergence, of primary accessory olfactory neurons. Neuron, 33, 1-20. Stowers, L., Holy, T., Meister, M., Dulac, C. and Koetnges, G. (2002). Loss of sex discrimination and male-male aggression in mice deficient in TRP2. Science, 295, 1493-1500. Dulac, C., Fraser, S. and Starling, B. (2001). Editorial Overview: New Technologies. Current Opinion in Neurobiology, 11, 591-592 Cao, Y. and Dulac, C. (2001). Profiling brain transcription: neurons learn a lesson from yeast. Current Opinion in Neurobiology, 11, 615-620. Pantages, E. and Dulac, C. (2000). A new family of candidate pheromone receptors in mammals. Neuron, 28, 835-845. Holy, T., Dulac, C. and Meister, M. (2000). Responses of vomeronasal neurons to natural stimuli. Science 289, 1569-1572. Dulac, C. (2000). Sensory coding of pheromone signals in mammals. Curr Opin Neurobiology, 10, 511-518. Dulac, C. (2000). The physiology of taste, vintage 2000. Cell, 100, 607-610. Liman, E., Corey, D., and Dulac, C. (1999). TRP2: A candidate transduction channel for mammalian pheromone sensory signaling. Proc. Natl. Acad. Sci. USA, 96, 5791-5796. Belluscio, L., Koentges, G., Axel, R. and Dulac, C. (1999). A Map of Pheromone Receptor Activation in the Mammalian Brain. Cell, 97, 209-220. Dulac, C. (1999). A Sweet Beginning (Preview). Neuron, 22, 204-206. Dulac, C. (1997). How Does the Brain Smell. Neuron, 19, 477-480. Herrada, G., and Dulac, C. (1997). A Novel Family of Putative Pheromone Receptors in Mammals with a Topographical Organized and Sexually Dimorphic Distribution. Cell, 90, 763-773. Mombaerts P., Wang F., Dulac C. , Chao S., Edmonson J., Nemes A., Mendelsohn M. and Axel R. (1996). Visualizing an Olfactory Sensory Map. Cell, 87, 675-686. Dulac C. and Axel R., (1995). A Novel Family of Genes encoding Putative Pheromone Receptors in Mammals. Cell, 83, 195-206. |
