title: Retinoic acid deficiency impairs the vestibular function.
abstract: The retinaldehyde dehydrogenase 3 (Raldh3) gene encodes a major retinoic acid synthesizing enzyme and is highly expressed in the inner ear during embryogenesis. We found that mice deficient in Raldh3 bear severe impairment in vestibular functions. These mutant mice exhibited spontaneous circling/tilted behaviors and performed poorly in several vestibular-motor function tests. In addition, video-oculography revealed a complete loss of the maculo-ocular reflex and a significant reduction in the horizontal angular vestibulo-ocular reflex, indicating that detection of both linear acceleration and angular rotation were compromised in the mutants. Consistent with these behavioral and functional deficiencies, morphological anomalies, characterized by a smaller vestibular organ with thinner semicircular canals and a significant reduction in the number of otoconia in the saccule and the utricle, were consistently observed in the Raldh3 mutants. The loss of otoconia in the mutants may be attributed, at least in part, to significantly reduced expression of Otop1, which encodes a protein known to be involved in calcium regulation in the otolithic organs. Our data thus reveal a previously unrecognized role of Raldh3 in structural and functional development of the vestibular end organs.
authors.affiliation: IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), BP 10142, Illkirch F-67404, France. romand@igbmc.fr
authors.forename: Raymond
authors.initials: R
authors.lastname: Romand
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krezel
authors.forename: Mathieu
authors.initials: M
authors.lastname: Beraneck
authors.forename: Laura
authors.initials: L
authors.lastname: Cammas
authors.forename: Valérie
authors.initials: V
authors.lastname: Fraulob
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Eri
authors.initials: E
authors.lastname: Hashino
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000704:Analysis of Variance; D000818:Animals; D001526:Behavioral Symptoms / Q000209:etiology / Q000235:genetics; D004622:Embryo, Mammalian; D005133:Eye Movements / Q000187:drug effects / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D021621:Imaging, Three-Dimensional; D007527:Isoenzymes / Q000172:deficiency; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010037:Otolithic Membrane / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D012027:Reflex, Vestibulo-Ocular / Q000187:drug effects* / Q000235:genetics*; D050697:Retinal Dehydrogenase / Q000172:deficiency; D013550:Swimming; D014212:Tretinoin / Q000494:pharmacology*; D014724:Vestibular Function Tests; D014722:Vestibule, Labyrinth / Q000503:physiopathology* / Q000648:ultrastructure; D014741:Video Recording; D014802:Vitamin A Deficiency / Q000209:etiology / Q000473:pathology*; D016138:Walking / Q000502:physiology
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; C508905:retinaldehyde dehydrogenase 3, mouse
references.citation: PLoS One. 2013;8(1):e53520
references.pmid: 23301081
references.citation: Hear Res. 1999 Sep;135(1-2):56-60
references.pmid: 10491954
references.citation: Physiol Rev. 2000 Jul;80(3):1021-54
references.pmid: 10893430
references.citation: J Assoc Res Otolaryngol. 2006 Jun;7(2):151-9
references.pmid: 16718609
references.citation: Vision Res. 2004 Dec;44(28):3401-10
references.pmid: 15536008
references.citation: J Neurophysiol. 1976 Sep;39(5):996-1008
references.pmid: 824414
references.citation: Annu Rev Neurosci. 2008;31:125-50
references.pmid: 18338968
references.citation: J Comp Neurol. 2004 Jan 19;468(4):587-95
references.pmid: 14689488
references.citation: Curr Protoc Neurosci. 2001 Aug;Chapter 8:Unit 8.12
references.pmid: 18428540
references.citation: Development. 1998 Feb;125(4):621-34
references.pmid: 9435283
references.citation: J Neurophysiol. 2003 Jul;90(1):155-64
references.pmid: 12843307
references.citation: Eur J Biochem. 2000 Jul;267(14):4315-24
references.pmid: 10880953
references.citation: Curr Top Dev Biol. 2003;57:261-91
references.pmid: 14674484
references.citation: Dev Biol. 1998 Dec 1;204(1):136-50
references.pmid: 9851848
references.citation: Hear Res. 2004 May;191(1-2):34-40
references.pmid: 15109702
references.citation: Hear Res. 1998 Aug;122(1-2):60-70
references.pmid: 9714575
references.citation: Chem Biol Interact. 2003 Feb 1;143-144:201-10
references.pmid: 12604205
references.citation: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7772-6
references.pmid: 8052659
references.citation: Mech Dev. 2000 Jul;95(1-2):283-9
references.pmid: 10906479
references.citation: J Comp Neurol. 2007 Oct 10;504(5):519-32
references.pmid: 17701983
references.citation: J Neurophysiol. 2005 Nov;94(5):3487-96
references.pmid: 16079198
references.citation: PLoS Biol. 2011 Jan 18;9(1):e1000582
references.pmid: 21267068
references.citation: Nat Protoc. 2010 Jan;5(1):177-90
references.pmid: 20057387
references.citation: J Anat. 1972 Nov;113(Pt 2):241-50
references.pmid: 4664235
references.citation: Brain Res. 2008 Feb 8;1193:57-66
references.pmid: 18178173
references.citation: Neurotoxicology. 2008 Nov;29(6):1107-13
references.pmid: 18840465
references.citation: J Assoc Res Otolaryngol. 2005 Dec;6(4):297-310
references.pmid: 16235133
references.citation: Invest Ophthalmol Vis Sci. 2010 Jan;51(1):623-30
references.pmid: 19696183
references.citation: Hum Mol Genet. 2003 Apr 1;12(7):777-89
references.pmid: 12651873
references.citation: Am J Otolaryngol. 1980 Nov;1(5):400-10
references.pmid: 7457761
references.citation: Rev Neurosci. 2004;15(1):75-87
references.pmid: 15046200
references.citation: Brain Res. 2006 May 26;1091(1):47-57
references.pmid: 16600187
references.citation: J Comp Neurol. 2006 Jun 10;496(5):643-54
references.pmid: 16615129
references.citation: Brain Res. 2006 May 26;1091(1):58-74
references.pmid: 16529728
references.citation: PLoS Genet. 2011 Sep;7(9):e1002307
references.pmid: 21980308
references.citation: BMC Genet. 2010 Jul 16;11:68
references.pmid: 20637105
references.citation: Prog Brain Res. 2008;171:503-8
references.pmid: 18718346
references.citation: Nat Genet. 1999 Apr;21(4):444-8
references.pmid: 10192400
references.citation: Cereb Cortex. 2002 Dec;12(12):1244-53
references.pmid: 12427676
references.citation: Gene Expr Patterns. 2004 Mar;4(2):123-33
references.pmid: 15161092
references.citation: Mech Dev. 2002 Jan;110(1-2):165-71
references.pmid: 11744377
references.citation: Mol Cell Biol. 2010 Jan;30(1):231-44
references.pmid: 19884340
references.citation: Nat Rev Genet. 2008 Jul;9(7):541-53
references.pmid: 18542081
references.citation: Cell. 2008 Sep 19;134(6):921-31
references.pmid: 18805086
references.citation: J Neurophysiol. 2010 Dec;104(6):3439-50
references.pmid: 20554841
references.citation: Development. 2005 Nov;132(21):4789-800
references.pmid: 16207763
references.citation: Otolaryngol Head Neck Surg. 2005 Jun;132(6):916-23
references.pmid: 15944564
references.citation: Neurosci Biobehav Rev. 2010 Jan;34(1):31-49
references.pmid: 19607857
references.citation: J Neurophysiol. 1971 Jul;34(4):635-60
references.pmid: 5000362
references.citation: J Physiol. 1943 Mar 25;101(4):389-407
references.pmid: 16991574
references.citation: Behav Brain Res. 2007 Jun 18;180(2):218-25
references.pmid: 17442411
references.citation: Development. 2000 Jan;127(1):75-85
references.pmid: 10654602
references.citation: J Neurosci. 1995 Nov;15(11):7201-16
references.pmid: 7472475
references.citation: Development. 2012 Mar;139(5):843-58
references.pmid: 22318625
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14036-41
references.pmid: 14623956
references.citation: Ergeb Anat Entwicklungsgesch. 1969;42(1):1-113
references.pmid: 5310109
references.citation: PLoS One. 2012;7(7):e40414
references.pmid: 22808156
references.citation: Physiol Genomics. 2008 Aug 15;34(3):243-55
references.pmid: 18505770
references.citation: Methods Mol Biol. 2006;326:61-87
references.pmid: 16780194
references.citation: Scan Electron Microsc. 1986;(Pt 4):1681-94
references.pmid: 3810031
references.citation: Neurobiol Dis. 2001 Feb;8(1):69-77
references.pmid: 11162241
references.citation: J Neurophysiol. 2007 Sep;98(3):1549-65
references.pmid: 17625061
references.citation: Biol Cell. 2005 Oct;97(10):787-98
references.pmid: 15730345
references.citation: J Physiol. 2007 Sep 15;583(Pt 3):923-43
references.pmid: 17627998
references.citation: J Neurophysiol. 1972 Nov;35(6):978-87
references.pmid: 4631840
references.citation: N Engl J Med. 1985 Oct 3;313(14):837-41
references.pmid: 3162101