title: Matrix recruitment and calcium sequestration for spatial specific otoconia development.
abstract: Otoconia are bio-crystals anchored to the macular sensory epithelium of the utricle and saccule in the inner ear for motion sensing and bodily balance. Otoconia dislocation, degeneration and ectopic calcification can have detrimental effects on balance and vertigo/dizziness, yet the mechanism underlying otoconia formation is not fully understood. In this study, we show that selected matrix components are recruited to form the crystal matrix and sequester Ca(2+) for spatial specific formation of otoconia. Specifically, otoconin-90 (Oc90) binds otolin through both domains (TH and C1q) of otolin, but full-length otolin shows the strongest interaction. These proteins have much higher expression levels in the utricle and saccule than other inner ear epithelial tissues in mice. In vivo, the presence of Oc90 in wildtype (wt) mice leads to an enrichment of Ca(2+) in the luminal matrices of the utricle and saccule, whereas absence of Oc90 in the null mice leads to drastically reduced matrix-Ca(2+). In vitro, either Oc90 or otolin can increase the propensity of extracellular matrix to calcify in cell culture, and co-expression has a synergistic effect on calcification. Molecular modeling and sequence analysis predict structural features that may underlie the interaction and Ca(2+)-sequestering ability of these proteins. Together, the data provide a mechanism for the otoconial matrix assembly and the role of this matrix in accumulating micro-environmental Ca(2+) for efficient CaCO(3) crystallization, thus uncover a critical process governing spatial specific otoconia formation.
authors.affiliation: Vestibular Neurogenetics Laboratory, Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Xing
authors.initials: X
authors.lastname: Zhao
authors.forename: Yinfang
authors.initials: Y
authors.lastname: Xu
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Quanyuan
authors.initials: Q
authors.lastname: He
authors.forename: Yunxia Wang
authors.initials: YW
authors.lastname: Lundberg
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002119:Calcium Carbonate / Q000737:chemistry / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003051:Cochlea / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D041681:NIH 3T3 Cells; D010037:Otolithic Membrane / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012444:Saccule and Utricle / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C512837:Oc90 protein, mouse; D002119:Calcium Carbonate; D002118:Calcium