title: Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium.
abstract: The olfactory epithelium (OE) is one of the few tissues to undergo constitutive neurogenesis throughout the mammalian lifespan. It is composed of multiple cell types including olfactory sensory neurons (OSNs) that are readily replaced by two populations of basal stem cells, frequently dividing globose basal cells and quiescent horizontal basal cells (HBCs). However, the precise mechanisms by which these cells mediate OE regeneration are unclear. Here, we show for the first time that the HBC subpopulation of basal stem cells uniquely possesses primary cilia that are aligned in an apical orientation in direct apposition to sustentacular cell end feet. The positioning of these cilia suggests that they function in the detection of growth signals and/or differentiation cues. To test this idea, we generated an inducible, cell type-specific Ift88 knock-out mouse line (K5rtTA;tetOCre;Ift88(fl/fl)) to disrupt cilia formation and maintenance specifically in HBCs. Surprisingly, the loss of HBC cilia did not affect the maintenance of the adult OE but dramatically impaired the regeneration of OSNs following lesion. Furthermore, the loss of cilia during development resulted in a region-specific decrease in neurogenesis, implicating HBCs in the establishment of the OE. Together, these results suggest a novel role for primary cilia in HBC activation, proliferation, and differentiation.
  
  
  CONCLUSIONS
  We show for the first time the presence of primary cilia on a quiescent population of basal stem cells, the horizontal basal cells (HBCs), in the olfactory epithelium (OE). Importantly, our data demonstrate that cilia on HBCs are necessary for regeneration of the OE following injury. Moreover, the disruption of HBC cilia alters neurogenesis during the development of the OE, providing evidence that HBCs participate in the establishment of this tissue. These data suggest that the mechanisms of penetrance for ciliopathies in the OE extend beyond that of defects in olfactory sensory neurons and may include alterations in OE maintenance and regeneration.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5632.
authors.forename: Ariell M
authors.initials: AM
authors.lastname: Joiner
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida, College of Medicine, Gainesville, Florida 32610-0267.
authors.forename: Warren W
authors.initials: WW
authors.lastname: Green
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida, College of Medicine, Gainesville, Florida 32610-0267.
authors.forename: Jeremy C
authors.identifier: http://orcid.org/0000-0001-8155-7166
authors.initials: JC
authors.lastname: McIntyre
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, and.
authors.forename: Benjamin L
authors.identifier: http://orcid.org/0000-0003-2323-8313
authors.initials: BL
authors.lastname: Allen
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: James E
authors.initials: JE
authors.lastname: Schwob
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5632, Department of Pharmacology & Therapeutics, University of Florida, College of Medicine, Gainesville, Florida 32610-0267, martensj@ufl.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Martens
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002923:Cilia / Q000235:genetics*; D004318:Doxycycline / Q000008:administration & dosage; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism; D008558:Melphalan / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051842:Olfactory Marker Protein / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology / Q000293:injuries*; D012038:Regeneration / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005719:gamma-Globulins / Q000378:metabolism
chemical_list: D020727:ADP-Ribosylation Factors; D051792:Basic Helix-Loop-Helix Proteins; D004318:Doxycycline; D049452:Green Fluorescent Proteins; D056466:Histone Demethylases; D008558:Melphalan; D009419:Nerve Tissue Proteins; D051842:Olfactory Marker Protein; D025521:Tumor Suppressor Proteins; D014446:Tyrosine 3-Monooxygenase; D005719:gamma-Globulins; C560093:Arl13b protein, mouse; C499317:Ascl1 protein, mouse; C045927:K-18 conjugate; C497598:Omp protein, mouse; C490898:Tg737Rpw protein, mouse; C504076:KDM1a protein, mouse
keywords: cilia; neurogenesis; olfaction; olfactory sensory neuron; stem cells