title: Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis.
abstract: Cellular heterogeneity hinders the extraction of functionally significant results and inference of regulatory networks from wide-scale expression profiles of complex mammalian organs. The mammalian inner ear consists of the auditory and vestibular systems that are each composed of hair cells, supporting cells, neurons, mesenchymal cells, other epithelial cells, and blood vessels. We developed a novel protocol to sort auditory and vestibular tissues of newborn mouse inner ears into their major cellular components. Transcriptome profiling of the sorted cells identified cell type-specific expression clusters. Computational analysis detected transcription factors and microRNAs that play key roles in determining cell identity in the inner ear. Specifically, our analysis revealed the role of the Zeb1/miR-200b pathway in establishing epithelial and mesenchymal identity in the inner ear. Furthermore, we detected a misregulation of the ZEB1 pathway in the inner ear of Twirler mice, which manifest, among other phenotypes, malformations of the auditory and vestibular labyrinth. The association of misregulation of the ZEB1/miR-200b pathway with auditory and vestibular defects in the Twirler mutant mice uncovers a novel mechanism underlying deafness and balance disorders. Our approach can be employed to decipher additional complex regulatory networks underlying other hearing and balance mouse mutants.
authors: Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, Baltimore, Maryland, United States of America. rhertzano@smail.umaryland.edu
authors: Ronna
authors: R
authors: Hertzano
authors: Ran
authors: R
authors: Elkon
authors: Kiyoto
authors: K
authors: Kurima
authors: Annie
authors: A
authors: Morrisson
authors: Siaw-Lin
authors: SL
authors: Chan
authors: Michelle
authors: M
authors: Sallin
authors: Andrew
authors: A
authors: Biedlingmaier
authors: Douglas S
authors: DS
authors: Darling
authors: Andrew J
authors: AJ
authors: Griffith
authors: David J
authors: DJ
authors: Eisenman
authors: Scott E
authors: SE
authors: Strome
mesh_terms: D000818:Animals; D003638:Deafness / Q000235:genetics / Q000378:metabolism; D007758:Ear, Inner / Q000033:anatomy & histology / Q000196:embryology*; D004847:Epithelial Cells / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology / Q000196:embryology; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009024:Morphogenesis / Q000235:genetics*; D014722:Vestibule, Labyrinth / Q000196:embryology; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; C541554:Mirn96 microRNA, mouse; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1