title: Differential timing of neurogenesis underlies dorsal-ventral topographic projection of olfactory sensory neurons.
abstract: BACKGROUND
  The mammalian primary olfactory system has a spatially-ordered projection in which olfactory sensory neurons (OSNs) located in the dorsomedial (DM) and ventrolateral (VL) region of the olfactory epithelium (OE) send their axons to the dorsal and ventral region of the olfactory bulb (OB), respectively. We previously found that OSN axonal projections occur sequentially, from the DM to the VL region of the OE. The differential timing of axonal projections is important for olfactory map formation because early-arriving OSN axons secrete guidance cues at the OB to help navigate late-arriving OSN axons. We hypothesized that the differential timing of axonal projections is regulated by the timing of OSN neurogenesis. To test this idea, we investigated spatiotemporal patterns of OSN neurogenesis during olfactory development.
  
  
  RESULTS
  To determine the time of OSN origin, we used two thymidine analogs, BrdU and EdU, which can be incorporated into cells in the S-phase of the cell-cycle. We injected these two analogs at different developmental time points and analyzed distribution patterns of labeled OSNs. We found that OSNs with different dates of origin were differentially distributed in the OE. The majority of OSNs generated at the early stage of development were located in the DM region of the OE, whereas OSNs generated at the later stage of development were preferentially located in the VL region of the OE.
  
  
  CONCLUSIONS
  These results indicate that the number of OSNs is sequentially increased from the DM to the VL axis of the OE. Moreover, the temporal sequence of OSN proliferation correlates with that of axonal extension and emergence of glomerular structures in the OB. Thus, we propose that the timing of OSN neurogenesis regulates that of OSN axonal projection and thereby helps preserve the topographic order of the olfactory glomerular map along the dorsal-ventral axis of the OB.
authors.affiliation: Division of Innate Immunity, Department of Microbiology and Immunology, the Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan.
authors.lastname: Eerdunfu
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ihara
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Bao
authors.initials: B
authors.lastname: Ligao
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, 113-0033, Japan.|Center for Information and Neural Networks, National Institute of Information and Communications Technology, Suita City, Osaka, 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, 113-0033, Japan. haruki-t@mol.f.u-tokyo.ac.jp.|Japan Science and Technology Agency (JST), PRESTO, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan. haruki-t@mol.f.u-tokyo.ac.jp.
authors.forename: Haruki
authors.identifier: http://orcid.org/0000-0003-4911-4060
authors.initials: H
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000071437:Axon Guidance; D001369:Axons / Q000502:physiology*; D051379:Mice; D055495:Neurogenesis; D009830:Olfactory Bulb / Q000196:embryology*; D009831:Olfactory Mucosa / Q000196:embryology; D018034:Olfactory Receptor Neurons / Q000502:physiology*
keywords: Neural circuit formation; Neurogenesis; Olfactory receptor; Olfactory sensory neuron; Topographic map; Zonal organization