title: The Stimulus-Dependent Gradient of Cyp26B1+ Olfactory Sensory Neurons Is Necessary for the Functional Integrity of the Olfactory Sensory Map.
abstract: 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 DM(high)-VL(low) 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.
  
  
  CONCLUSIONS
  The mouse olfactory sensory map is functionally wired according to precise axonal projections of spatially organized classes of olfactory sensory neurons in the nose. The genetically controlled mechanisms that regulate the development of the olfactory sensory map are beginning to be elucidated. Little is known about mechanisms by which sensory stimuli shape the organization of the map after birth. We show that a stimulus-dependent gradient of a retinoic acid-inactivating enzyme Cyp26B1 modifies the composition, localization, and axonal projections of olfactory sensory neuron classes. The mechanism is novel and suggests the interesting possibility that local vitamin A metabolism could also be a mediator of stimulus-dependent modifications of precise spatial connectivity in other parts of the nervous system.
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå SE90187, Sweden.
authors.forename: Hande
authors.initials: H
authors.lastname: Login
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå SE90187, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Håglin
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå SE90187, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Berghard
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå SE90187, Sweden Staffan.Bohm@umu.se.
authors.forename: Staffan
authors.initials: S
authors.lastname: Bohm
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism; D000367:Age Factors; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones / Q000378:metabolism; D001931:Brain Mapping; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007641:Keratolytic Agents / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D051842:Olfactory Marker Protein / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology*; D050697:Retinal Dehydrogenase / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; D016227:Benzoquinones; D006657:Histones; D007527:Isoenzymes; D007641:Keratolytic Agents; C108768:Ncam2 protein, mouse; D019006:Neural Cell Adhesion Molecules; D051842:Olfactory Marker Protein; C497598:Omp protein, mouse; C004532:quinone; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D001616:beta-Galactosidase
keywords: activity dependent; odorant receptors; olfactory sensory neurons; retinoic acid; sensory map; vitamin A