title: Ephrin-B2 governs morphogenesis of endolymphatic sac and duct epithelia in the mouse inner ear.
abstract: Control over ionic composition and volume of the inner ear luminal fluid endolymph is essential for normal hearing and balance. Mice deficient in either the EphB2 receptor tyrosine kinase or the cognate transmembrane ligand ephrin-B2 (Efnb2) exhibit background strain-specific vestibular-behavioral dysfunction and signs of abnormal endolymph homeostasis. Using various loss-of-function mouse models, we found that Efnb2 is required for growth and morphogenesis of the embryonic endolymphatic epithelium, a precursor of the endolymphatic sac (ES) and duct (ED), which mediate endolymph homeostasis. Conditional inactivation of Efnb2 in early-stage embryonic ear tissues disrupted cell proliferation, cell survival, and epithelial folding at the origin of the endolymphatic epithelium. This correlated with apparent absence of an ED, mis-localization of ES ion transport cells relative to inner ear sensory organs, dysplasia of the endolymph fluid space, and abnormally formed otoconia (extracellular calcite-protein composites) at later stages of embryonic development. A comparison of Efnb2 and Notch signaling-deficient mutant phenotypes indicated that these two signaling systems have distinct and non-overlapping roles in ES/ED development. Homozygous deletion of the Efnb2 C-terminus caused abnormalities similar to those found in the conditional Efnb2 null homozygote. Analyses of fetal Efnb2 C-terminus deletion heterozygotes found mis-localized ES ion transport cells only in the genetic background exhibiting vestibular dysfunction. We propose that developmental dysplasias described here are a gene dose-sensitive cause of the vestibular dysfunction observed in EphB-Efnb2 signaling-deficient mice.
authors.affiliation: Section on Sensory Cell Regeneration and Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rafts@nidcd.nih.gov.
authors.forename: Steven
authors.initials: S
authors.lastname: Raft
authors.affiliation: Laboratory of Biomineralization, Institute of Biomedical Sciences, CCS, Universidade Federal do Rio de Janeiro, RJ 21941-902, Brazil.
authors.forename: Leonardo R
authors.initials: LR
authors.lastname: Andrade
authors.affiliation: Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Shao
authors.affiliation: Department of Orthopedics, Gifu University, Gifu City 501-1194, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Henkemeyer
authors.affiliation: Section on Sensory Cell Regeneration and Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: wud@nidcd.nih.gov.
authors.forename: Doris K
authors.initials: DK
authors.lastname: Wu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004712:Endolymphatic Sac / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D036388:Ephrin-B2 / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D009024:Morphogenesis / Q000235:genetics; D011247:Pregnancy; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
chemical_list: D036388:Ephrin-B2; D051880:Receptors, Notch
keywords: Cre-mediated gene inactivation; Deafness; Dlx5; Embryo; Endolymph; Endolymphatic duct; Endolymphatic sac; EphB2; Ephrin-B2; Eph–ephrin; Fluid homeostasis; Foxi1; Gbx2; Growth; Inner ear; Morphogenesis; Mouse; Notch; Otoconia; Otocyst; Pendrin; Proliferation; Proton-translocating ATPase; Signaling; Slc26a4; Vestibular