Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance
Tóm tắt
The defining feature of the main olfactory system in mice is that each olfactory sensory neuron expresses only one of more than a thousand different odorant receptor genes. Axons expressing the same odorant receptor converge onto a small number of targets in the olfactory bulb such that each glomerulus is made up of axon terminals expressing just one odorant receptor. It is thought that this precision in axon targeting is required to maintain highly refined odor discrimination. We previously showed that β3GnT2−/− mice have severe developmental and axon guidance defects. The phenotype of these mice is similar to adenylyl cyclase 3 (AC3) knockout mice largely due to the significant down-regulation of AC3 activity in β3GnT2−/− neurons. Microarray analysis reveals that nearly one quarter of all odorant receptor genes are down regulated in β3GnT2−/− mice compared to controls. Analysis of OR expression by quantitative PCR and in situ hybridization demonstrates that the number of neurons expressing some odorant receptors, such as mOR256-17, is increased by nearly 60% whereas for others such as mOR28 the number of neurons is decreased by more than 75% in β3GnT2−/− olfactory epithelia. Analysis of axon trajectories confirms that many axons track to inappropriate targets in β3GnT2−/− mice, and some glomeruli are populated by axons expressing more than one odorant receptor. Results show that mutant mice perform nearly as well as control mice in an odor discrimination task. In addition, in situ hybridization studies indicate that the expression of several activity dependent genes is unaffected in β3GnT2−/− olfactory neurons. Results presented here show that many odorant receptors are under-expressed in β3GnT2−/− mice and further demonstrate that additional axon subsets grow into inappropriate targets or minimally innervate glomeruli in the olfactory bulb. Odor evoked gene expression is unchanged and β3GnT2−/− mice exhibit a relatively small deficit in their ability to discriminate divergent odors. Results suggest that despite the fact that β3GnT2−/− mice have decreased AC3 activity, decreased expression of many ORs, and display many axon growth and guidance errors, odor-evoked activity in cilia of mutant olfactory neurons remains largely intact.
Tài liệu tham khảo
Mombaerts P, Wang F, Dulac C, Chao SK, Nemes A, Mendelsohn M, Edmondson J: Visualizing an olfactory sensory map. Cell. 1996, 87: 675-686. 10.1016/S0092-8674(00)81387-2.
Vassar R, Chao SK, Sitcheran R, Nuñez JM, Vosshall LB, Axel R: Topographic organization of sensory projections to the olfactory bulb. Cell. 1994, 79: 981-991. 10.1016/0092-8674(94)90029-9.
Wang F, Nemes A, Mendelsohn M, Axel R: ORs govern the formation of a precise topographic map. Cell. 1998, 93: 47-60. 10.1016/S0092-8674(00)81145-9.
Imai T, Suzuki M, Sakano H: Odorant receptor-derived cAMP signals direct axonal targeting. Science. 2006, 314: 657-661. 10.1126/science.1131794.
Serizawa S, Miyamichi K, Takeuchi H, Yamagishi Y, Suzuki M, Sakano H: A neuronal identity code for the odorant receptor-specific and activity-dependent axon sorting. Cell. 2006, 127: 1057-1069. 10.1016/j.cell.2006.10.031.
Henion TR, Faden AA, Knott TK, Schwarting GA: β3GnT2 maintains adenylyl cyclase-3 signaling and axon guidance molecule expression in the olfactory epithelium. J Neurosci. 2011, 31: 6576-6586. 10.1523/JNEUROSCI.0224-11.2011.
Imai T, Sakano H: Odorant receptor-mediated signaling in the mouse. Curr Opin Neurobiol. 2008, 18: 251-260. 10.1016/j.conb.2008.07.009.
Henion TR, Raitcheva D, Grosholz R, Biellmann F, Skarnes WC, Hennet T, Schwarting GA: Beta1-3-N-Acetylglucosaminytransferase 1 glycosylation is required for axon pathfinding by olfactory sensory neurons. J Neurosci. 2005, 25: 1894-1903. 10.1523/JNEUROSCI.4654-04.2005.
Schwarting GA, Henion TR: Lactosamine differentially affects olfactory sensory neuron projections to the olfactory bulb. Dev Neurobiol. 2007, 67: 1627-1640. 10.1002/dneu.20536.
Trinh K, Storm DR: Vomeronasal organ detects odorants in absence of signaling through main olfactory epithelium. Nat Neurosci. 2003, 6: 519-525.
Chesler AT, Zou DJ, Le Pichon CE, Peterlin ZA, Matthews GA, Pei X, Miller MC, Firestein S: A G protein/cAMP signal cascade is required for axonal convergence into olfactory glomeruli. Proc Natl Acad Sci USA. 2007, 104: 1039-1044. 10.1073/pnas.0609215104.
Col JA, Matsuo T, Storm DR, Rodriguez I: Adenylyl cyclase-dependent axonal targeting in the olfactory system. Development. 2007, 134: 2481-2489. 10.1242/dev.006346.
Imai T, Yamazaki T, Kobayakawa R, Kobayakawa K, Abe T, Suzuki M, Sakano H: Pre-target axon sorting establishes the neural map topography. Science. 2009, 325: 585-590. 10.1126/science.1173596.
Wong ST, Trinh K, Hacker B, Chan GC, Lowe G, Gaggar A, Xia Z, Gold GH, Storm DR: Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron. 2000, 27: 487-497. 10.1016/S0896-6273(00)00060-X.
Iwema CL, Fang H, Kurtz DB, Youngentob SL, Schwob JE: Odorant receptor expression patterns are restored in lesion-recovered rat olfactory epithelium. J Neurosci. 2004, 14: 356-369.
Strotmann J, Levai O, Fleischer J, Schwartzenbacher K, Breer H: Olfactory receptor proteins in axonal processes of chemosensory neurons. J Neurosci. 2004, 24: 7754-7761. 10.1523/JNEUROSCI.2588-04.2004.
Oztokatli H, Hornberg M, Berghard A, Bohm S: Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons. FASEB J. 2012, 26: 617-627. 10.1096/fj.11-192450.
Bennett MK, Kulaga HM, Reed RR: Odor-evoked gene regulation and visualization in olfactory receptor neurons. Mol Cell Neurosci. 2010, 43: 353-362. 10.1016/j.mcn.2010.01.002.
Fleischmann A, Shykind BM, Sosulski DL, Franks KM, Glinka ME, Mei DF, Sun Y, Kirkland J, Mendelsohn M, Albers MW, Axel R: Mice with a “monoclonal nose”: perturbations in an olfactory map impair odor discrimination. Neuron. 2008, 60: 1068-1081. 10.1016/j.neuron.2008.10.046.
Zou DJ, Feinstein P, Rivers AL, Mathews GA, Kim A, Greer CA, Mombaerts P, Firestein S: Postnatal refinement of peripheral olfactory projections. Science. 2004, 304: 1976-1979. 10.1126/science.1093468.
Zhao H, Reed RR: X inactivation of the OCNC1 channel gene reveals a role for activity-dependent competition in the olfactory system. Cell. 2001, 104: 651-660. 10.1016/S0092-8674(01)00262-8.
Serizawa S, Miyamichi K, Nakatani H, Suzuki M, Saito M, Yoshihara Y, Sakano H: Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse. Science. 2003, 302: 2088-2094. 10.1126/science.1089122.
Lewcock JW, Reed RR: A feedback mechanism regulates monoallelic odorant receptor expression. Proc Natl Acad Sci U S A. 2004, 101: 1069-1074. 10.1073/pnas.0307986100.
Shykind BM, Rohani SC, O’Donnell S, Nemes A, Mendelsohn M, Sun Y, Axel R, Barnea G: Gene switching and the stability of odorant receptor gene choice. Cell. 2004, 117: 801-815.
Lu X-CM, Slotnick BM: Olfaction in rats with extensive lesions of the olfactory bulb: Implications for odor coding. Neuroscience. 1998, 84: 849-866. 10.1016/S0306-4522(97)00520-4.
Cho JH, Prince JE, Cutforth T, Cloutier JF: The pattern of glomerular map formation defines responsiveness to aversive odorants in mice. J Neurosci. 2011, 31: 7920-7926. 10.1523/JNEUROSCI.2460-10.2011.
Ben-Chaim Y, Cheng MM, Yau K-Y: Unitary response of mouse olfactory receptor neurons. Proc Natl Acad Sci USA. 2011, 108: 822-827. 10.1073/pnas.1017983108.
Watt WC, Storm DR: Odorants stimulate the ERK/mitogen-activated protein kinase pathway and activate cAMP-response element-mediated transcription in olfactory sensory neurons. J Biol Chem. 2001, 276: 2047-2052.
Sakano H: Neural map formation in the mouse olfactory system. Neuron. 2010, 67: 530-542. 10.1016/j.neuron.2010.07.003.
Schwarting GA, Henion TR: Regulation and function of axon guidance and adhesion molecules during olfactory map formation. J Cell Biochem. 2011, 112: 2663-2671. 10.1002/jcb.23203.
Bakalyar HA, Reed RR: Identification of a specialized adenylyl cyclase that may mediate odorant detection. Science. 2000, 250: 1403-1406.
Kaneko-Goto T, Yoshihara S, Miyazaki H, Yoshihara Y: BIG-2 mediates olfactory axon convergence to target glomeruli. Neuron. 2008, 57: 834-846. 10.1016/j.neuron.2008.01.023.
Bishop GA, Berbari NF, Lewis J, Mykytyn K: Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol. 2007, 505: 562-571. 10.1002/cne.21510.
Pluznick JL, Rodriguez-Gil DJ, Hull M, Mistry K, Gattone V, Johnson CA, Weatherbee S, Greer CA, Caplan MJ: Renal cystic disease proteins play critical roles in the organization of the olfactory epithelium. PLoS One. 2001, 6: e19694-
Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ, García-Verdugo JM, Katsanis N, Hildebrandt F, Reiter JF: A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet. 2011, 43: 776-784. 10.1038/ng.891.
Maritan M, Monaco G, Zamparo I, Zaccolo M, Pozzan T, Lodovichi C: Odorant receptors at the growth cone are coupled to localized cAMP and Ca2+ increases. Proc Natl Acad Sci USA. 2009, 106: 3537-3542. 10.1073/pnas.0813224106.
Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, Leighton PA, Goodrich LV, Lu X, Avery BJ, Tate P, Dill K, Pangilinan E, Wakenight P, Tessier-Lavigne M, Skarnes WC: Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet. 2001, 28: 241-249. 10.1038/90074.
Barnea G, O’Donnell S, Mancia F, Sun X, Nemes A, Mendelsohn M, Axel R: Odorant receptors on axon termini in the brain. Science. 2004, 304: 1468-10.1126/science.1096146.
Smith DR, Striplin AM, Geller RB, Mailman JD, Lawler CP, Gallagher M: Behavioral assessment of mice lacking D1A dopamine receptors. Neuroscience. 1998, 85: 135-146. 10.1016/S0306-4522(97)00621-0.
Sklar P, Anholt RRH, Snyder SH: The odorant-sensitive adenylate cyclase of olfactory receptor cells: Differential stimulation by distinct classes of odorants. J Biol Chem. 1986, 261: 15538-15543.