Retinoic acid receptor and CNGA2 channel signaling are part of a regulatory feedback loop controlling axonal convergence and survival of olfactory sensory neurons.
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.
Department of Molecular Biology, Umeå University, Umeå, Sweden.
Hande
H
Öztokatli
Maria
M
Hörnberg
Anna
A
Berghard
Staffan
S
Bohm
D000818:Animals; D001369:Axons / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015870:Gene Expression; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000502:physiology*; D018035:Receptors, Odorant / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction
C518240:Cnga2 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; C474214:Kirrel3 protein, mouse; D008565:Membrane Proteins; D018035:Receptors, Odorant; D018168:Receptors, Retinoic Acid; D003577:Cytochrome P-450 Enzyme System; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase