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Bohm, Staffan
Publications (10 of 21) Show all publications
Maurya, D. K., Berghard, A. & Bohm, S. (2022). A multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins. Nature Communications, 13(1), Article ID 6889.
Open this publication in new window or tab >>A multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins
2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 6889Article in journal (Refereed) Published
Abstract [en]

Stimulus transduction in cilia of olfactory sensory neurons is mediated by odorant receptors, Gαolf, adenylate cyclase-3, cyclic nucleotide-gated and chloride ion channels. Mechanisms regulating trafficking and localization of these proteins in the dendrite are unknown. By lectin/immunofluorescence staining and in vivo correlative light-electron microscopy (CLEM), we identify a retinitis pigmentosa-2 (RP2), ESCRT-0 and synaptophysin-containing multivesicular organelle that is not part of generic recycling/degradative/exosome pathways. The organelle's intraluminal vesicles contain the olfactory transduction proteins except for Golf subunits Gγ13 and Gβ1. Instead, Gβ1 colocalizes with RP2 on the organelle’s outer membrane. The organelle accumulates in response to stimulus deprivation, while odor stimuli or adenylate cyclase activation cause outer membrane disintegration, release of intraluminal vesicles, and RP2/Gβ1 translocation to the base of olfactory cilia. Together, these findings reveal the existence of a dendritic organelle that mediates both stimulus-regulated storage of olfactory ciliary transduction proteins and membrane-delimited sorting important for G protein heterotrimerization.

Place, publisher, year, edition, pages
Nature Publishing Group, 2022
National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:umu:diva-201163 (URN)10.1038/s41467-022-34604-y (DOI)000882468500005 ()36371422 (PubMedID)2-s2.0-85141674177 (Scopus ID)
Funder
Umeå UniversitySwedish Society for Medical Research (SSMF)The Kempe Foundations, JCK-1619
Available from: 2022-11-22 Created: 2022-11-22 Last updated: 2023-09-05Bibliographically approved
Håglin, S., Bohm, S. & Berghard, A. (2021). Single or Repeated Ablation of Mouse Olfactory Epithelium by Methimazole. Bio-protocol, 11(8), Article ID e3983.
Open this publication in new window or tab >>Single or Repeated Ablation of Mouse Olfactory Epithelium by Methimazole
2021 (English)In: Bio-protocol, E-ISSN 2331-8325, Vol. 11, no 8, article id e3983Article in journal (Refereed) Published
Abstract [en]

Odor-detecting olfactory sensory neurons residing in the nasal olfactory epithelium (OE) are the only neurons in direct contact with the external environment. As a result, these neurons are subjected to chemical, physical, and infectious insults, which may be the underlying reason why neurogenesis occurs in the OE of adult mammals. This feature makes the OE a useful model for studying neurogenesis and neuronal differentiation, with the possibility for systemic as well as local administration of various compounds and infectious agents that may interfere with these cellular processes. Several different chemical compounds have been shown to cause toxic injury to the OE, which can be used for OE ablation. We, and others, have found that the systemic administration of the hyperthyroid drug, methimazole, reliably causes olfactotoxicity as a side effect. Here, we outline an OE lesioning protocol for single or repeated ablation by methimazole. A single methimazole administration can be used to study neuroepithelial regeneration and stem cell activation, while repeated ablation and regeneration of OE enable the study of tissue stem cell exhaustion and generation of tissue metaplasia.

Place, publisher, year, edition, pages
Bio-protocol, 2021
Keywords
Olfactory epithelium, Methimazole, Lesion, Regeneration, Tissue stem cell, Metaplasia
National Category
Neurosciences Cell and Molecular Biology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-187350 (URN)10.21769/BioProtoc.3983 (DOI)000642293100002 ()34124287 (PubMedID)2-s2.0-85115927484 (Scopus ID)
Funder
The Swedish Brain Foundation, FO20180195
Available from: 2021-09-09 Created: 2021-09-09 Last updated: 2022-09-15Bibliographically approved
Maurya, D. K. & Bohm, S. (2020). Activity-dependent regulation of translation in olfactory sensory neurons of naris- occluded mice. Paper presented at 29th Annual Meeting of the European-Chemoreception-Research-Organization (ECRO), SEP 11-14, 2019, Abdus Salam Int Ctr Theoret Phhys, Trieste, ITALY. Chemical Senses, 45(2), 142-143
Open this publication in new window or tab >>Activity-dependent regulation of translation in olfactory sensory neurons of naris- occluded mice
2020 (English)In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 45, no 2, p. 142-143Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2020
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-172831 (URN)000538788900074 ()
Conference
29th Annual Meeting of the European-Chemoreception-Research-Organization (ECRO), SEP 11-14, 2019, Abdus Salam Int Ctr Theoret Phhys, Trieste, ITALY
Available from: 2020-06-26 Created: 2020-06-26 Last updated: 2025-02-20Bibliographically approved
Håglin, S., Berghard, A. & Bohm, S. (2020). Increased Retinoic Acid Catabolism in Olfactory Sensory Neurons Activates Dormant Tissue-Specific Stem Cells and Accelerates Age-Related Metaplasia. Journal of Neuroscience, 40(21), 4116-4129
Open this publication in new window or tab >>Increased Retinoic Acid Catabolism in Olfactory Sensory Neurons Activates Dormant Tissue-Specific Stem Cells and Accelerates Age-Related Metaplasia
2020 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 40, no 21, p. 4116-4129Article in journal (Refereed) Published
Abstract [en]

The cellular and molecular basis of metaplasia and declining neurogenesis in the aging olfactory epithelium (OE) remains unknown. The horizontal basal cell (HBC) is a dormant tissue-specific stem cell presumed to only be forced into self-renewal and differentiation by injury. Here we analyze male and female mice and show that HBCs also are activated with increasing age as well as non-cell-autonomously by increased expression of the retinoic acid-degrading enzyme CYP26B1. Activating stimuli induce HBCs throughout OE to acquire a rounded morphology and express IP3R3, which is an inositol-1,4,5-trisphosphate receptor constitutively expressed in stem cells of the adjacent respiratory epithelium. Odor/air stimulates CYP26B1 expression in olfactory sensory neurons mainly located in the dorsomedial OE, which is spatially inverse to ventrolateral constitutive expression of the retinoic acid-synthesizing enzyme (RALDH1) in supporting cells. In ventrolateral OE, HBCs express low p63 levels and preferentially differentiate instead of self-renewing when activated. When activated by chronic CYP26B1 expression, repeated injury, or old age, ventrolateral HBCs diminish in number and generate a novel type of metaplastic respiratory cell that is RALDH(-) and secretes a mucin-like mucus barrier protein (Fc gamma BP). Conversely, in the dorsomedial OE, CYP26B1 inhibits injury-induced and age-related replacement of RALDH(-) supporting cells with RALDH1(+) ciliated respiratory cells. Collectively, these results support the concept that inositol-1,4,5-trisphosphate type 3 receptor signaling in HBCs, together with altered retinoic acid metabolism within the niche, promote HBC lineage commitment toward two types of respiratory cells that will maintain epithelial barrier function once the capacity to regenerate OE cells ceases.

Place, publisher, year, edition, pages
Society for Neuroscience, 2020
Keywords
aging, inositol-1, 4, 5-triphosphate, metaplasia, olfactory epithelium, retinoic acid, stem cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-173813 (URN)10.1523/JNEUROSCI.2468-19.2020 (DOI)000535694700005 ()32385093 (PubMedID)2-s2.0-85085266059 (Scopus ID)
Available from: 2020-08-03 Created: 2020-08-03 Last updated: 2023-03-24Bibliographically approved
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 and Genomics
Identifiers
urn:nbn:se:umu:diva-141992 (URN)10.1073/pnas.1708321114 (DOI)000414127400026 ()29078327 (PubMedID)2-s2.0-85032730617 (Scopus ID)
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2025-02-07Bibliographically 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)2-s2.0-84933182530 (Scopus ID)
Available from: 2014-05-20 Created: 2014-05-20 Last updated: 2023-03-23Bibliographically 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)2-s2.0-84944081193 (Scopus ID)
Available from: 2015-12-04 Created: 2015-12-04 Last updated: 2023-03-24Bibliographically 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)2-s2.0-84864758823 (Scopus ID)
Funder
Swedish Research Council
Available from: 2012-05-13 Created: 2012-05-13 Last updated: 2023-03-24Bibliographically 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)2-s2.0-84856545944 (Scopus ID)
Available from: 2012-05-29 Created: 2012-05-29 Last updated: 2023-03-24Bibliographically 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)2-s2.0-62849125587 (Scopus ID)
Available from: 2010-03-23 Created: 2010-03-23 Last updated: 2023-03-24Bibliographically approved
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