title: Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.
abstract: The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media. During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis. The relation of this developmental process to stria vascularis function is currently unknown. In characterizing the molecular differentiation of developing peripheral auditory structures, we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium. Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte-derived intermediate cells in the stria vascularis. Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling. In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages. These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies.
  
  
  
  We found the roles of hepatocyte growth factor (HGF) signaling in stria vascularis development for the first time and that lack of HGF signaling in the inner ear leads to profound hearing loss in the mouse. Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97. Our findings reveal an additional example of context-dependent c-MET signaling diversity, required here for proper cellular invasion developmentally that is essential for specific aspects of auditory-related organogenesis.
authors.affiliation: Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, Zilkha Neurogenetic Institute, and.
authors.forename: Shumei
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, Zilkha Neurogenetic Institute, and.
authors.forename: Toru
authors.identifier: 0000-0002-5977-0056
authors.initials: T
authors.lastname: Miwa
authors.affiliation: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and Program in Developmental Neurogenetics, Institute for the Developing Mind, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California 90027.
authors.forename: Hsiao-Huei
authors.identifier: 0000-0002-9538-9017
authors.initials: HH
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and Program in Developmental Neurogenetics, Institute for the Developing Mind, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California 90027.
authors.forename: Pat
authors.identifier: 0000-0002-9717-1695
authors.initials: P
authors.lastname: Levitt
authors.affiliation: Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, Zilkha Neurogenetic Institute, and takahiro.ohyama@med.usc.edu.
authors.forename: Takahiro
authors.identifier: 0000-0001-6237-7389
authors.initials: T
authors.lastname: Ohyama
mesh_terms: D000818:Animals; D003051:Cochlea / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006309:Hearing; D034381:Hearing Loss / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D008297:Male; D008544:Melanocytes / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D013316:Stria Vascularis / Q000473:pathology
chemical_list: D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: auditory; melanocyte; neural crest; receptor tyrosine kinase; stria vascularis