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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    • "Differentiation via LSD1 Downregulation The intriguing observation that Adcy3 expression is mutually exclusive with LSD1 expression and depends upon OR expression prompted us to test whether this protein plays a role in the downregulation of LSD1 and the stabilization of OR choice. Adcy3 is the main adenylyl cyclase in OSNs, and previous reports have shown that Adcy3 KO OSNs have severe targeting defects (Chesler et al., 2007; Col et al., 2007; Zou et al., 2007). A role of Adcy3 in stabilization of OR expression could account for these targeting deficits, together with activity-dependent processes that regulate axon guidance. "
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    ABSTRACT: The molecular mechanisms regulating olfactory receptor (OR) expression in the mammalian nose are not yet understood. Here, we identify the transient expression of histone demethylase LSD1 and the OR-dependent expression of adenylyl cyclase 3 (Adcy3) as requirements for initiation and stabilization of OR expression. As a transcriptional coactivator, LSD1 is necessary for desilencing and initiating OR transcription, but as a transcriptional corepressor, it is incompatible with maintenance of OR expression, and its downregulation is imperative for stable OR choice. Adcy3, a sensor of OR expression and a transmitter of an OR-elicited feedback, mediates the downregulation of LSD1 and promotes the differentiation of olfactory sensory neurons (OSNs). This novel, three-node signaling cascade locks the epigenetic state of the chosen OR, stabilizes its singular expression, and prevents the transcriptional activation of additional OR alleles for the life of the neuron.
    Cell 07/2013; 154(2):325-36. DOI:10.1016/j.cell.2013.06.039 · 33.12 Impact Factor
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    • "Cyclic AMP is a key molecule regulating growth cone dynamics (Song & Poo, 2001), and experimental manipulation of the ratio of cAMP to cGMP determines the responsiveness of axonal growth cones to guidance cues (Nishiyama et al., 2003). In the embryonic brain cAMP is critical for proper axonal pathfinding of olfactory sensory neurons (Chesler et al., 2007). In migrating neurons, alteration in the levels of cAMP decreases the migratory speed of cerebellar granule cells (Cuzon et al., 2008) and modulates the effects of serotonin on migrating cortical interneurons (Riccio et al., 2009). "
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    ABSTRACT: Monoamines such as serotonin and dopamine have been shown to regulate cortical interneuron migration but very little is known regarding noradrenaline. Similarly to other monoamines, noradrenaline is detected during embryonic cortical development and adrenergic receptors are expressed in transient embryonic zones of the pallium that contain migrating neurons. Evidence of a functional role for the adrenergic system in interneuron migration is lacking. In this study we first investigated the expression pattern of adrenergic receptors in mouse cortical interneuron subtypes preferentially derived from the caudal ganglionic eminences, and found that they expressed different subtypes of adrenergic receptors. To directly monitor the effects of adrenergic receptor stimulation on interneuron migration we used time-lapse recordings in cortical slices and observed that alpha2 adrenergic receptors (adra2) receptor activation inhibits the migration of cortical interneurons in a concentration-dependent and reversible manner. Furthermore, we observed that following adra2 activation the directionality of migrating interneurons was significantly modified, suggesting that adra2 stimulation could modulate their responsiveness to guidance cues. Finally the distribution of cortical interneurons was altered in vivo in adra2a/2c-knockout mice. These results support the general hypothesis that adrenergic dysregulation occurring during embryonic development alters cellular processes involved in the formation of cortical circuits.
    European Journal of Neuroscience 07/2012; 36(7):2879-2887. DOI:10.1111/j.1460-9568.2012.08231.x · 3.67 Impact Factor
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    • "As noted before, only the targeted disruption of ORs and AC3 disturbs the initial formation of glomeruli while downstream signaling components such as Gαolf and CNGA2 are dispensable for grossly normal map formation developmentally. This in part is explained by redundancy in G-protein expression in the OE (Imai et al., 2006; Chesler et al., 2007). Whether such signals emanate from intrinsic stimuli or spontaneous activity, it will be important to show that each OR-expressing population is defined by specific level of cAMP-signaling that directs Nrp1 expression and glomerular targeting. "
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    ABSTRACT: The olfactory system presents a practical model for investigating basic mechanisms involved in patterning connections between peripheral sensory neurons and central targets. Our understanding of olfactory map formation was advanced greatly by the discovery of cAMP signaling as an important determinant of glomerular positioning in the olfactory bulb. Additionally, several cell adhesion molecules have been identified recently that are proposed to regulate homotypic interactions among projecting axons. From these studies a model has emerged to partially explain the wiring of axons from widely dispersed neuron populations in the nasal cavity to relatively stereotyped glomerular positions. These advances have revitalized interest in axon guidance molecules in establishing olfactory topography, but also open new questions regarding how these patterns of guidance cues are established and function, and what other pathways, such as glycosylation, might be involved. This review summarizes the current state of this field and the important molecules that impact on cAMP-dependent mechanism in olfactory axon guidance.
    Journal of Cellular Biochemistry 10/2011; 112(10):2663-71. DOI:10.1002/jcb.23203 · 3.37 Impact Factor
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