umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Bohm, Staffan
Publications (10 of 17) Show all publications
Maurya, D. K., Bohm, S. & Alenius, M. (2017). Hedgehog signaling regulates ciliary localization of mouse odorant receptors. Proceedings of the National Academy of Sciences of the United States of America, 114(44), E9386-E9394
Open this publication in new window or tab >>Hedgehog signaling regulates ciliary localization of mouse odorant receptors
2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 44, p. E9386-E9394Article in journal (Refereed) Published
Abstract [en]

The ciliary localization of odorant receptors (ORs) is evolutionary conserved and essential for olfactory transduction. However, how the transport of ORs is regulated in mammalian olfactory sensory neurons is poorly understood. Here we demonstrate that odorant responsiveness and OR transport is regulated by the Hedgehog pathway. OR transport is inhibited by conditional gene inactivation of the Hedgehog signal mediator Smoothened (Smo) as well as by systemic administration of the Smo inhibitor vismodegib, a clinically used anticancer drug reported to distort smell perception in patients. The ciliary phenotype of Smo inhibition is haploinsufficient, cell autonomous, and correlates with the accumulation of OR-containing putative transport vesicles in the cytosol. The Smo-dependent OR transport route works in parallel with a low basal transport of vesicle containing both ORs and other olfactory transduction components. These findings both define a physio logical function of Hedgehog signaling in olfaction and provide an important evolutionary link between olfaction and the requirement of a ciliary compartment for Hedgehog signaling.

Place, publisher, year, edition, pages
National Academy of Sciences, 2017
Keywords
odorant receptors, Hedgehog pathway, Smoothened, vismodegib, cilia transport
National Category
Genetics
Identifiers
urn:nbn:se:umu:diva-141992 (URN)10.1073/pnas.1708321114 (DOI)000414127400026 ()29078327 (PubMedID)
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2018-06-09Bibliographically approved
Login, H., Butowt, R. & Bohm, S. (2015). Activity-dependent and graded BACE1 expression in the olfactory epithelium is mediated by the retinoic acid metabolizing enzyme CYP26B1. Brain Structure and Function, 220(4), 2143-2157
Open this publication in new window or tab >>Activity-dependent and graded BACE1 expression in the olfactory epithelium is mediated by the retinoic acid metabolizing enzyme CYP26B1
2015 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, no 4, p. 2143-2157Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer, 2015
Keywords
Cyp26B1, BACE1, Retinoic acid, Olfactory sensory map, Gene expression, Development
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-89034 (URN)10.1007/s00429-014-0783-z (DOI)000356874700018 ()24797530 (PubMedID)
Available from: 2014-05-20 Created: 2014-05-20 Last updated: 2018-06-07Bibliographically approved
Login, H., Håglin, S., Berghard, A. & Bohm, S. (2015). The Stimulus-Dependent Gradient of Cyp26B1+ Olfactory Sensory Neurons Is Necessary for the Functional Integrity of the Olfactory Sensory Map. Journal of Neuroscience, 35(40), 13807-13818
Open this publication in new window or tab >>The Stimulus-Dependent Gradient of Cyp26B1+ Olfactory Sensory Neurons Is Necessary for the Functional Integrity of the Olfactory Sensory Map
2015 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 40, p. 13807-13818Article in journal (Refereed) Published
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.

Keywords
activity dependent, odorant receptors, olfactory sensory neurons, retinoic acid, sensory map, vitamin A
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-112309 (URN)10.1523/JNEUROSCI.2247-15.2015 (DOI)000366050900024 ()26446231 (PubMedID)
Available from: 2015-12-04 Created: 2015-12-04 Last updated: 2019-08-13Bibliographically approved
Berghard, A., Hägglund, A.-C., Bohm, S. & Carlsson, L. (2012). Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons. The FASEB Journal, 26(8), 3464-3472
Open this publication in new window or tab >>Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons
2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 8, p. 3464-3472Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2012
Keywords
mouse embryo development, gonadotropin-releasing hormone neurons, puberty phenotype
National Category
Neurosciences Developmental Biology
Identifiers
urn:nbn:se:umu:diva-55206 (URN)10.1096/fj.12-206193 (DOI)
Funder
Swedish Research Council
Available from: 2012-05-13 Created: 2012-05-13 Last updated: 2018-06-08Bibliographically approved
Öztokatli, H., Hörnberg, M., Berghard, A. & Bohm, S. (2012). Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons. The FASEB Journal, 26(2), 617-627
Open this publication in new window or tab >>Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons
2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 2, p. 617-627Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2012
Keywords
retinoids, neuronal activity, caspase-3, Kirrel-2, Neuropilin-1
National Category
Cell and Molecular Biology
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-55746 (URN)10.1096/fj.11-192450 (DOI)000300485700015 ()22009938 (PubMedID)
Available from: 2012-05-29 Created: 2012-05-29 Last updated: 2018-06-08Bibliographically approved
Vedin, V., Molander, M., Bohm, S. & Berghard, A. (2009). Regional differences in olfactory epithelial homeostasis in the adult mouse. Journal of Comparative Neurology, 513(4), 375-384
Open this publication in new window or tab >>Regional differences in olfactory epithelial homeostasis in the adult mouse
2009 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 513, no 4, p. 375-384Article in journal (Refereed) Published
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.

Keywords
olfaction, neurogenesis, proliferation, zone, postnatal
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32741 (URN)10.1002/cne.21973 (DOI)19177519 (PubMedID)
Available from: 2010-03-23 Created: 2010-03-23 Last updated: 2018-06-08Bibliographically approved
Hörnberg, M., Gussing, F., Berghard, A. & Bohm, S. (2009). Retinoic acid selectively inhibits death of basal vomeronasal neurons during late stage of neural circuit formation. Journal of Neurochemistry, 110(4), 1263-1275
Open this publication in new window or tab >>Retinoic acid selectively inhibits death of basal vomeronasal neurons during late stage of neural circuit formation
2009 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 110, no 4, p. 1263-1275Article in journal (Refereed) Published
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.

Keywords
caspase, cell survival, Kirrel, olfactory, retinoic acid, vomeronasal
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32707 (URN)10.1111/j.1471-4159.2009.06216.x (DOI)000268221500012 ()19519663 (PubMedID)
Funder
Swedish Research Council Formas, K2008-63X-20726-01-3
Available from: 2010-03-23 Created: 2010-03-23 Last updated: 2019-01-24Bibliographically approved
Hägglund, M., Berghard, A., Strotmann, J. & Bohm, S. (2006). Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.. Journal of Neuroscience, 26(12), 3281-3291
Open this publication in new window or tab >>Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.
2006 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 12, p. 3281-3291Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-16510 (URN)10.1523/JNEUROSCI.4955-05.2006 (DOI)16554478 (PubMedID)
Available from: 2007-10-04 Created: 2007-10-04 Last updated: 2018-06-09
Norlin, M., Vedin, V., Bohm, S. & Berghard, A. (2005). Odorant-dependent, spatially restricted induction of c-fos in the olfactory epithelium of the mouse.. Journal of Neurochemistry, 96(6), 1594-602
Open this publication in new window or tab >>Odorant-dependent, spatially restricted induction of c-fos in the olfactory epithelium of the mouse.
2005 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 96, no 6, p. 1594-602Article in journal (Refereed) Published
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.

National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-16531 (URN)10.1111/j.1471-4159.2005.03159.x (DOI)15935076 (PubMedID)
Available from: 2007-10-05 Created: 2007-10-05 Last updated: 2018-06-09
Gussing, F. & Bohm, S. (2004). NQO1 activity in the main and the accessory olfactory systems correlates with the zonal topography of projection maps. European Journal of Neuroscience, 19(9), 2511-2518
Open this publication in new window or tab >>NQO1 activity in the main and the accessory olfactory systems correlates with the zonal topography of projection maps
2004 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 19, no 9, p. 2511-2518Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2004
Keywords
DT-diaphorase, gene expression, odorant receptors, olfactory, sensory map, vomeronasal
National Category
Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:umu:diva-4156 (URN)10.1111/j.0953-816X.2004.03331.x (DOI)000221126700016 ()15128404 (PubMedID)
Available from: 2004-11-22 Created: 2004-11-22 Last updated: 2019-01-23Bibliographically approved
Organisations

Search in DiVA

Show all publications