A G protein/cAMP signal cascade is required for axonal convergence into olfactory glomeruli

Department of Biological Sciences, Columbia University, New York, New York, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2007; 104(3):1039-44. DOI: 10.1073/pnas.0609215104
Source: PubMed

ABSTRACT The mammalian odorant receptors (ORs) comprise a large family of G protein-coupled receptors that are critical determinants of both the odorant response profile and the axonal identity of the olfactory sensory neurons in which they are expressed. Although the pathway by which ORs activate odor transduction is well established, the mechanism by which they direct axons into proper glomerular relationships remains unknown. We have developed a gain-of-function approach by using injection of retroviral vectors into the embryonic olfactory epithelium to study the ORs' contribution to axon guidance. By ectopically expressing ORs, we demonstrate that functional OR proteins induce axonal coalescence. Furthermore, ectopic expression of Galpha mutants reveals that activation of the signal transduction cascade is sufficient to cause axonal convergence into glomeruli. Analysis of Galpha subunit expression indicates that development and odorant transduction use separate transduction pathways. Last, we establish that the generation of cAMP through adenylyl cyclase 3 is necessary to establish proper axonal identity. Our data point to a model in which axonal sorting is accomplished by OR stimulation of cAMP production by coupling to Galphas.

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    ABSTRACT: cAMP signaling affects a large number of the developmental processes needed for the construction of the CNS, including cell differentiation, axon outgrowth, response to guidance molecules or modulation of synaptic connections. This points to a key role of adenylate cyclases (ACs), the synthetic enzymes of cAMP, for neural development. ACs exist as 10 different isoforms, which are activated by distinct signaling pathways. The implication of specific AC isoforms in neural wiring was only recently demonstrated in mouse mutants, knockout (KO) for different AC isoforms, AC1, AC3, AC5, AC8 and soluble (s)AC/AC10. These studies stressed the importance of three of these isoforms, as sensors of neural activity that could modify the survival of neurons (sAC), axon outgrowth (sAC), or the response of axons to guidance molecules such as ephrins (AC1) or semaphorins (AC3). We summarize here the current knowledge on the role of these ACs for the development of sensory maps, in the somatosensory, visual and olfactory systems, which have been the most extensively studied. In these systems, AC1/AC3 KO revealed targeting mistakes due to the defective pruning and lack of discrimination of incoming axons to signals present in target structures. In contrast, no changes in cell differentiation, survival or axon outgrowth were noted in these mutants, suggesting a specificity of cAMP production routes for individual cellular processes within a given neuron. Further studies indicate that the subcellular localization of ACs could be key to their specific role in axon targeting and may explain their selective roles in neuronal wiring.
    European Journal of Neuroscience 03/2014; 39(11). DOI:10.1111/ejn.12543 · 3.67 Impact Factor
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    ABSTRACT: The olfactory system provides a great opportunity to explore the mechanisms that underlie the formation and function of neural circuits because of the simplicity of its structure. Olfactory sensory neurons (OSNs) located in the peripheral olfactory epithelium (OE) take part in the initial formation and function of glomeruli in the olfactory bulb (OB) inside the central nervous system. Glomeruli are key in the process of transduction of olfactory information, as they constitute a map in the OB that sorts the different types of odorant inputs. This odorant categorization allows proper olfactory perception, and it is achieved through the anatomical organization and function of the different glomerular circuits. Once formed, glomeruli keep the capacity to undergo diverse plasticity processes, which is unique among the different neural circuits of the central nervous system. In this context, through the expression and function of the odorant receptors (ORs), OSNs perform two of the most important roles in the olfactory system: transducing odorant information to the nervous system and initiating the development of the glomerular map to organize olfactory information. This review addresses essential information that has emerged in recent years about the molecular basis of these processes.
    Neural Plasticity 2015:975367. DOI:10.1155/2015/975367 · 3.60 Impact Factor


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