BIG-2 Mediates Olfactory Axon Convergence to Target Glomeruli

Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Neuron (Impact Factor: 15.05). 04/2008; 57(6):834-46. DOI: 10.1016/j.neuron.2008.01.023
Source: PubMed


Olfactory sensory neurons expressing a given odorant receptor converge axons onto a few topographically fixed glomeruli in the olfactory bulb, leading to establishment of the odor map. Here, we report that BIG-2/contactin-4, an axonal glycoprotein belonging to the immunoglobulin superfamily, is expressed in a subpopulation of mouse olfactory sensory neurons. A mosaic pattern of glomerular arrangement is observed with strongly BIG-2-positive, weakly positive, and negative axon terminals in the olfactory bulb, which is overlapping but not identical with those of Kirrel2 and ephrin-A5. There is a close correlation between the BIG-2 expression level and the odorant receptor choice in individual sensory neurons. In BIG-2-deficient mice, olfactory sensory neurons expressing a given odorant receptor frequently innervate multiple glomeruli at ectopic locations. These results suggest that BIG-2 is one of the axon guidance molecules crucial for the formation and maintenance of functional odor map in the olfactory bulb.

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    • "Contactin-4 Is Expressed by RGCs that Target AOS Nuclei To explore the molecular signals controlling development of parallel eye-to-brain circuits, we screened the expression patterns of IgG superfamily proteins in retinorecipient targets and identified Contactin-4 (CNTN4) as a candidate. CNTN4 belongs to a small family of axon-associated cell adhesion molecules within the IgG superfamily that has six Ig domains and four fibronectin type III domains and is glycophosphatidylinositol (GPI)-anchored to the plasma membrane (Yoshihara et al., 1995; Kaneko-Goto et al., 2008; reviewed in Shimoda and Watanabe, 2009). Labeling of retinorecipient targets by intravitreal injections of cholera toxin beta (CTb-594) followed by staining of tissue sections with an antibody specific for CNTN4 (Kaneko-Goto et al., 2008; Figures S1E and S1H) revealed that it was selectively expressed in AOS targets: it was present at high levels in the developing NOT (Figures 1D–1F) and at lower levels in the MTNd and MTNv (Figures 1G–1I). "
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    ABSTRACT: The mammalian eye-to-brain pathway includes more than 20 parallel circuits, each consisting of precise long-range connections between specific sets of retinal ganglion cells (RGCs) and target structures in the brain. The mechanisms that drive assembly of these parallel connections and the functional implications of their specificity remain unresolved. Here we show that in the absence of contactin 4 (CNTN4) or one of its binding partners, amyloid precursor protein (APP), a subset of direction-selective RGCs fail to target the nucleus of the optic tract (NOT)-the accessory optic system (AOS) target controlling horizontal image stabilization. Conversely, ectopic expression of CNTN4 biases RGCs to arborize in the NOT, and that process also requires APP. Our data reveal critical and novel roles for CNTN4/APP in promoting target-specific axon arborization, and they highlight the importance of this process for functional development of a behaviorally relevant parallel visual pathway. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 05/2015; 86(4). DOI:10.1016/j.neuron.2015.04.005 · 15.05 Impact Factor
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    • "Other Cntns have been less studied. Cntn4 acts as an axon guidance molecule in the mouse olfactory neural circuitry where it controls the establishment of odor maps (Kaneko-Goto et al., 2008). Cntn5 contributes to the development of glutamatergic neurons in the rat auditory brainstem (Toyoshima et al., 2009a), while Cntn6 orientates the growth of apical dendrites of deep layer cortical pyramidal neurons (Ye et al., 2008) and controls the normal projection and branching of axons of the corticospinal tract during development (Huang et al., 2012). "
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    ABSTRACT: The neural cell-adhesion molecules contactin 4, contactin 5 and contactin 6 are involved in brain development, and disruptions in contactin genes may confer increased risk for autism spectrum disorders (ASD). We describe a co-culture of rat cortical neurons and HEK293 cells overexpressing and delivering the secreted forms of rat contactin 4-6. We quantified their effects on the length and branching of neurites. Contactin 4-6 effects were different depending on the contactin member and duration of co-culture. At 4 days in culture, contactin 4 and -6 increased the length of neurites, while contactin 5 increased the number of roots. Up to 8 days in culture, contactin 6 progressively increased the length of neurites while contactin 5 was more efficient on neurite branching. We studied the molecular sites of interaction between human contactin 4, -5 or -6 and the human Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a contactin partner, by modeling their 3D structures. As compared to contactin 4, we observed differences in the Ig2 and Ig3 domains of contactin 5 and -6 with the appearance of an omega loop that could adopt three distinct conformations. However, interactive residues between human contactin 4-6 and PTPRG were strictly conserved. We did not observe any differences in PTPRG binding on contactin 5 and -6 either. Our data suggest that the differential contactin effects on neurite outgrowth do not result from distinct interactions with PTPRG. A better understanding of the contactin cellular properties should help elucidate their roles in ASD.
    Biology Open 03/2013; 2(3):324-34. DOI:10.1242/bio.20133343 · 2.42 Impact Factor
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    • "These glomeruli, which are functional based on the expression of VGlut2, may have been overlooked in the past using these two markers. This finding adds to the complexity observed in the olfactory bulb, where it seems that each glomerulus is unique considering not only the expression of only one odorant receptor, but also for the graded expression of specific sets of adhesion-related molecules [7], [8]. Second, Dvl-1 expression was restricted to the most dorsal recess of the nasal cavity. "
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    ABSTRACT: Olfactory sensory neurons (OSNs) project their axons from the olfactory epithelium toward the olfactory bulb (OB) in a heterogeneous and unsorted arrangement. However, as the axons approach the glomerular layer of the OB, axons from OSNs expressing the same odorant receptor (OR) sort and converge to form molecularly homogeneous glomeruli. Axon guidance cues, cell adhesion molecules, and OR induced activity have been implicated in the final targeting of OSN axons to specific glomeruli. Less understood, and often controversial, are the mechanisms used by OSN axons to initially navigate from the OE toward the OB. We previously demonstrated a role for Wnt and Frizzled (Fz) molecules in OSN axon extension and organization within the olfactory nerve. Building on that we now turned our attention to the downstream signaling cascades from Wnt-Fz interactions. Dishevelled (Dvl) is a key molecule downstream of Fz receptors. Three isoforms of Dvl with specific as well as overlapping functions are found in mammals. Here, we show that Dvl-1 expression is restricted to OSNs in the dorsal recess of the nasal cavity, and labels a unique subpopulation of glomeruli. Dvl-2 and Dvl-3 have a widespread distribution in both the OE and OB. Both Dvl-1 and Dvl-2 are associated with intra-glomerular pre-synaptic OSN terminals, suggesting a role in synapse formation/stabilization. Moreover, because Dvl proteins were observed in all OSN axons, we hypothesize that they are important determinants of OSN cell differentiation and axon extension.
    PLoS ONE 02/2013; 8(2):e56561. DOI:10.1371/journal.pone.0056561 · 3.23 Impact Factor
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