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  • 1.
    Berghard, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hägglund, Anna-Carin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 8, 3464-3472 p.Article in journal (Refereed)
    Abstract [en]

    Inactivation of the LIM-homeodomain 2 gene (Lhx2) results in a severe defect in specification of olfactory sensory neurons (OSNs). However, the ramifications of lack of Lhx2-dependent OSN specification for formation of the primary olfactory pathway have not been addressed, since mutant mice die in utero. We have analyzed prenatal and postnatal consequences of conditionally inactivating Lhx2 selectively in OSNs. A cell-autonomous effect is that OSN axons cannot innervate their target, the olfactory bulb. Moreover, the lack of Lhx2 in OSNs causes unpredicted, non-cell-autonomous phenotypes. First, the olfactory bulb shows pronounced hypoplasia in adults, and the data suggest that innervation by correctly specified OSNs is necessary for adult bulb size and organization. Second, absence of an olfactory nerve in the conditional mutant reveals that the vomeronasal nerve is dependent on olfactory nerve formation. Third, the lack of a proper vomeronasal nerve prevents migration of gonadotropin-releasing hormone (GnRH) cells the whole distance to their final positions in the hypothalamus during embryo development. As adults, the conditional mutants do not pass puberty, and these findings support the view of an exclusive nasal origin of GnRH neurons in the mouse. Thus, Lhx2 in OSNs is required for functional development of three separate systems.—Berghard, A., Hägglund, A.-C., Bohm, S., and Carlsson, L. Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.

  • 2.
    Gussing, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    NQO1 activity in the main and the accessory olfactory systems correlates with the zonal topography of projection maps2004In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 19, no 9, 2511-2518 p.Article in journal (Refereed)
    Abstract [en]

    The mouse olfactory epithelium (OE) is divided into spatial zones, each containing neurons expressing zone-specific subsets of odorant receptor genes. Likewise, the vomeronasal (VN) organ is organized into apical and basal subpopulations of neurons expressing different VN receptor gene families. Axons projecting from the different OE zones and VN subpopulations form synapses within circumscribed regions in the glomerular layer of the olfactory bulb (OB) and accessory olfactory bulb (AOB), respectively. We here show that mature neurons in one defined zone selectively express NADPH:quinone oxidoreductase (NQO1), an enzyme that catalyses reduction of quinones. Immunohistochemistry and in situ hybridization analyses show non-overlapping expression of NQO1 and the Rb8 neural cell adhesion molecule (RNCAM/OCAM) in OE and axon terminals within glomeruli of the OB. In addition, NQO1 immunoreactivity reveals selective, zone-specific axon fasciculation in the olfactory nerve. VN subpopulations do not show complementary patterns of RNCAM and NQO1 immunoreactivity, instead both genes are co-expressed in apical VN neurons that project to the rostral AOB. These results indicate that one division of both the accessory and the main olfactory projection maps are composed of sensory neurons that are specialized to reduce environmental and/or endogenously produced quinones via an NQO1-dependent mechanism. The role of NQO1 in bioactivation of quinoidal drugs also points to a connection between zone-specific NQO1 expression and zone-specific toxicity of certain olfactory toxins.

  • 3.
    Hägglund, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Strotmann, J
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 12, 3281-3291 p.Article in journal (Refereed)
  • 4.
    Hörnberg, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gussing, Fredrik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Medicine, Molecular Biology.
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Retinoic acid selectively inhibits death of basal vomeronasal neurons during late stage of neural circuit formation.2009In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 110, no 4, 1263-1275 p.Article in journal (Refereed)
    Abstract [en]

    In mouse, sexual, aggressive, and social behaviors are influenced by G protein-coupled vomeronasal receptor signaling in two distinct subsets of vomeronasal sensory neurons (VSNs): apical and basal VSNs. In addition, G protein-signaling by these receptors inhibits developmental death of VSNs. We show that cells of the vomeronasal nerve express the retinoic acid (RA) synthesizing enzyme retinal dehydrogenase 2. Analyses of transgenic mice with VSNs expressing a dominant-negative RA receptor indicate that basal VSNs differ from apical VSNs with regard to a transient wave of RA-regulated and caspase 3-mediated cell death during the first postnatal week. Analyses of G-protein subunit deficient mice indicate that RA and vomeronasal receptor signaling combine to regulate postnatal expression of Kirrel-2 (Kin of IRRE-like), a cell adhesion molecule regulating neural activity-dependent formation of precise axonal projections in the main olfactory system. Collectively, the results indicate a novel connection between pre-synaptic RA receptor signaling and neural activity-dependent events that together regulate neuronal survival and maintenance of synaptic contacts.

  • 5. Kaluza, Jan F
    et al.
    Gussing, Fredrik
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Breer, Heinz
    Strotmann, Jörg
    Olfactory receptors in the mouse septal organ.2004In: J Neurosci Res, ISSN 0360-4012, Vol. 76, no 4, 442-52 p.Article in journal (Refereed)
    Abstract [en]

    In this study we have identified a repertoire of chemosensory receptors expressed in the septal organ (SO). The results suggest that septal organ neurons are specified to express receptor genes belonging to class II olfactory receptors that are also expressed in the main olfactory epithelium. We found no evidence for the expression of members from the vomeronasal receptor gene families. In the SO, no topography analogous to the receptor expression zones of the main olfactory epithelium was evident. The majority of identified receptors corresponds to genes with restricted expression in the medial and lateral zones of the main olfactory epithelium. This coincides with the expression of olfactory cell adhesion molecule (OCAM) throughout the SO, which is considered as a marker for the medial-lateral zones. In contrast, NADPH:quinone oxidoreductase 1 expression, a characteristic marker for the dorsal zone, was lacking in the SO. Most of the receptor types were found to be expressed in rather few SO neurons; as an exception, the receptor mOR244-3 was observed in a very high proportion of cells. Although a very high fraction of SO neurons expressed mOR244-3, we found no evidence for the coexpression of different receptors in individual cells. Copyright 2004 Wiley-Liss, Inc.

  • 6.
    Kolterud, Åsa
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology.
    Alenius, Mattias
    Umeå University, Faculty of Medicine, Molecular Biology.
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity.2004In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 21, 5319-5326 p.Article in journal (Refereed)
    Abstract [en]

    Progenitor cells in the mouse olfactory epithelium generate over a thousand subpopulations of neurons, each expressing a unique odorant receptor (OR) gene. This event is under the control of spatial cues, since neurons in different epithelial regions are restricted to express region-specific subsets of OR genes. We show that progenitors and neurons express the LIM-homeobox gene Lhx2 and that neurons in Lhx2-null mutant embryos do not diversify into subpopulations expressing different OR genes and other region-restricted genes such as Nqo1 and Ncam2. Lhx2-/- embryos have, however, a normal distribution of Mash1-positive and neurogenin 1-positive neuronal progenitors that leave the cell cycle, acquire pan-neuronal traits and form axon bundles. Increased cell death in combination with increased expression of the early differentiation marker Neurod1, as well as reduced expression of late differentiation markers (Galphaolf and Omp), suggests that neuronal differentiation in the absence of Lhx2 is primarily inhibited at, or immediate prior to, onset of OR expression. Aberrant regional expression of early and late differentiation markers, taken together with unaltered region-restricted expression of the Msx1 homeobox gene in the progenitor cell layer of Lhx2-/- embryos, shows that Lhx2 function is not required for all aspects of regional specification of progenitors and neurons. Thus, these results indicate that a cell-autonomous function of Lhx2 is required for differentiation of progenitors into a heterogeneous population of individually and regionally specified mature olfactory sensory neurons.

  • 7.
    Login, Hande
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Butowt, Rafal
    Bohm, Staffan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Activity-dependent and graded BACE1 expression in the olfactory epithelium is mediated by the retinoic acid metabolizing enzyme CYP26B12015In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, no 4, 2143-2157 p.Article in journal (Refereed)
    Abstract [en]

    It is well established that environmental influences play a key role in sculpting neuronal connectivity in the brain. One example is the olfactory sensory map of topographic axonal connectivity. While intrinsic odorant receptor signaling in olfactory sensory neurons (OSN) determines anterior-posterior counter gradients of the axonal guidance receptors Neuropilin-1 and Plexin-A1, little is known about stimulus-dependent gradients of protein expression, which correlates with the functional organization of the olfactory sensory map along its dorsomedial (DM)-ventrolateral (VL) axis. Deficiency of the Alzheimer's β-secretase BACE1, which is expressed in a DM(low)-VL(high) gradient, results in OSN axon targeting errors in a DM > VL and gene dose-dependent manner. We show that expression of BACE1 and the all-trans retinoic acid (RA)-degrading enzyme Cyp26B1 form DM-VL counter gradients in the olfactory epithelium. Analyses of mRNA and protein levels in OSNs after naris occlusion, in mice deficient in the olfactory cyclic nucleotide-gated channel and in relation to onset of respiration, show that BACE1 and Cyp26B1 expression in OSNs inversely depend on neuronal activity. Overexpression of a Cyp26B1 or presence of a dominant negative RA receptor transgene selectively in OSNs, inhibit BACE1 expression while leaving the DM(low)-VL(high) gradient of the axonal guidance protein Neuropilin-2 intact. We conclude that stimulus-dependent neuronal activity can control the expression of the RA catabolic enzyme Cyp26B1 and downstream genes such as BACE1. This result is pertinent to an understanding of the mechanisms by which a topographic pattern of connectivity is achieved and modified as a consequence of graded gene expression and sensory experience.

  • 8.
    Login, Hande
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Håglin, Sofia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The Stimulus-Dependent Gradient of Cyp26B1+ Olfactory Sensory Neurons Is Necessary for the Functional Integrity of the Olfactory Sensory Map2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 40, 13807-13818 p.Article in journal (Refereed)
    Abstract [en]

    Stimulus-dependent expression of the retinoic acid-inactivating enzyme Cyp26B1 in olfactory sensory neurons (OSNs) forms a dorsomedial (DM)-ventrolateral (VL) gradient in the mouse olfactory epithelium. The gradient correlates spatially with different rates of OSN turnover, as well as the functional organization of the olfactory sensory map, into overlapping zones of OSNs that express different odorant receptors (ORs). Here, we analyze transgenic mice that, instead of a stimulus-dependent Cyp26B1 gradient, have constitutive Cyp26B1 levels in all OSNs. Starting postnatally, OSN differentiation is decreased and progenitor proliferation is increased. Initially, these effects are selective to the VL-most zone and correlate with reduced ATF5 expression and accumulation of OSNs that do not express ORs. Transcription factor ATF5 is known to stabilize OR gene choice via onset of the stimulus-transducing enzyme adenylyl cyclase type 3. During further postnatal development of Cyp26B1 mice, an anomalous DMhigh-VLlow expression gradient of adenylyl cyclase type 3 appears, which coincides with altered OR frequencies and OR zones. All OR zones expand ventrolaterally except for the VL-most zone, which contracts. The expansion results in an increased zonal overlap that is also evident in the innervation pattern of OSN axon terminals in olfactory bulbs. These findings together identify a mechanism by which postnatal sensory-stimulated vitamin A metabolism modifies the generation of spatially specified neurons and their precise topographic connectivity. The distributed patterns of vitamin A-metabolizing enzymes in the nervous system suggest the possibility that the mechanism may also regulate neuroplasticity in circuits other than the olfactory sensory map.

  • 9.
    Login, Hande
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Håglin, Sofia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bohm, Staffan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Spatial differences in activity-dependent neurogenesis and neuronal diversification in the olfactory epithelium is regulated by the retinoic acid-metabolizing enzyme Cyp26B1Manuscript (preprint) (Other academic)
  • 10.
    Norlin, Marianne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Alenius, Mattias
    Umeå University, Faculty of Medicine, Molecular Biology.
    Gussing, Fredrik
    Umeå University, Faculty of Medicine, Molecular Biology.
    Hägglund, Maria
    Umeå University, Faculty of Medicine, Molecular Biology.
    Vedin, Viktoria
    Umeå University, Faculty of Medicine, Molecular Biology.
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Molecular Biology.
    Evidence for gradients of gene expression correlating with zonal topography of the olfactory sensory map2001In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 18, no 3, 283-295 p.Article in journal (Refereed)
    Abstract [en]

    Signals regulating diversification of olfactory sensory neurons to express odorant receptors and other genes necessary for correct assembly of the olfactory sensory map persist in the olfactory epithelium of adult mouse. We have screened for genes with an expression pattern correlating with the topography odorant receptor-expression zones. The Msx1 homeobox gene and a semaphorin receptor (Neuropilin-2) showed graded expression patterns in the olfactory epithelium. The gradients of Msx1 and Neuropilin-2 expression in basal cells and neurons, respectively, correlated with expression of a retinoic acid-synthesizing enzyme (RALDH2) in lamina propria. A BMP-type I receptor (Alk6) showed a reverse gradient of expression in the supporting cells of the epithelium. Considering known functions of identified genes in cell specification and axon guidance this suggests that zonal division of the olfactory sensory map is maintained, during continuous neurogenesis, as a consequence of topographic counter gradients of positional information. Copyright 2001 Academic Press.

  • 11.
    Norlin, Marianne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vedin, Viktoria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Odorant-dependent, spatially restricted induction of c-fos in the olfactory epithelium of the mouse.2005In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 96, no 6, 1594-602 p.Article in journal (Refereed)
    Abstract [en]

    Volatile odorous chemicals are detected by around a thousand different G protein-coupled odorant receptors in the mouse. We demonstrated that exposure of the behaving mouse to odorant for a few minutes led to induction of the immediate early gene c-fos for several hours in a fraction of the olfactory sensory neurones in the nasal cavity. Associated with this odorant-specific induction event was activation of extracellular-regulated kinase (ERK)1/2 that preceded increased c-fos expression. The distribution of odorant-activated neurones mimicked the scattered and spatially limited distribution of neurones expressing a single odorant receptor gene. A small change in odorant chemical structure caused a zonal shift in the spatial distribution of activated neurones, suggesting that the gene expression change resulted from specific receptor interaction. Repeated exposure to odorant or use of different concentrations did not change the pattern of c-fos induction. These results indicate that odorant-induced c-fos expression can be used to visualize odorant representations in the olfactory epithelium that reflect late cellular events regulated by adequate odorant receptor stimulation.

  • 12.
    Vedin, Viktoria
    et al.
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Molander, Marie
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Regional differences in olfactory epithelial homeostasis in the adult mouse2009In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 513, no 4, 375-384 p.Article in journal (Refereed)
    Abstract [en]

    The olfactory sensory neurons in the nasal cavity of the adult mouse are organized into a few regions that differ in their molecular properties, as several classes of genes show regional expression. Most renowned is the fact that expression of each of hundreds of different odorant receptor genes is limited to one such region, or zone, of the olfactory neuroepithelial sheet. Zone differences are in place at birth, as exemplified here by the expression of neuronal progenitor marker Foxg1. We herein describe that an adult pattern showing regional differences in neurogenesis develops during the first few weeks of postnatal life which, e.g., is reflected in the temporal and regional regulation of the neuronal progenitor marker Ascl1. The most dorsomedial zone shows significantly fewer cells in S-phase in the adult but not in newborn mice by two different measures. Moreover, we show that there are regional differences in the relative differentiation, cell survival, and thickness of the olfactory epithelium. These findings are compatible with the view that zones are inherently distinct and that such differences contribute to generate regional differences in cellular homeostasis that in turn may modulate the capacity of a region to adjust to extrinsic influence.

  • 13.
    Öztokatli, Hande
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hörnberg, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berghard, Anna
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bohm, Staffan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 2, 617-627 p.Article in journal (Refereed)
    Abstract [en]

    Little is known about the identities and functions of extracellular signaling molecules that work in concert with neuronal activity to regulate refinement and maintenance of the mouse olfactory sensory map. We show that expression of a dominant negative retinoic acid receptor (RAR) in olfactory sensory neurons (OSNs) increased the number of glomeruli that incorrectly contained OSN axons expressing different odorant receptors. This phenotype became apparent postnatally, coincided with increased cell death, and was preceded by increased Neuropilin-1 and reduced Kirrel-2 expressions. Kirrel-2-mediated cell adhesion influences odorant receptor-specific axonal convergence and is regulated by odorant receptor signaling via the olfactory cyclic nucleotide-gated (CNG) ion channel. Accordingly, we found that inhibited RAR function correlated with reduced CNG channel expression. Naris occlusion experiments and analysis of CNG channel-deficient mice further indicated that RAR-regulated CNG channel levels influenced the intrinsic neuronal activity required for cell survival in the absence of odor stimulation. Finally, we showed that CNG channel activity regulated expression of the retinoic acid-degrading enzyme Cyp26B1. Combined, these results identify a novel homeostatic feedback mechanism involving retinoic acid metabolism and CNG channel activity, which influences glomerular homogeneity and maintenance of precisely connected OSNs.

1 - 13 of 13
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