Hepatocyte Growth Factor–c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing

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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.

SIGNIFICANCE STATEMENT 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.

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Author and article information

Journal

Journal ID (nlm-ta): J Neurosci

Journal ID (iso-abbrev): J. Neurosci

Journal ID (hwp): jneuro

Journal ID (pmc): jneurosci

Journal ID (publisher-id): J. Neurosci

Title: The Journal of Neuroscience

Publisher: Society for Neuroscience

ISSN (Print): 0270-6474

ISSN (Electronic): 1529-2401

Publication date (Print): 3 August 2016

Publication date PMC-release: 3 February 2017

Volume: 36

Issue: 31

Pages: 8200-8209

Affiliations

[1] ¹Tina and Rick Caruso Department of Otolaryngology–Head and Neck Surgery,

[2] ²Zilkha Neurogenetic Institute, and

[3] ³Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and

[4] ⁴Program in Developmental Neurogenetics, Institute for the Developing Mind, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California 90027

Author notes

Correspondence should be addressed to Takahiro Ohyama at the above address. takahiro.ohyama@ 123456med.usc.edu

Author contributions: T.O. designed research; S.S., T.M., and T.O. performed research; H.-H.W. and P.L. contributed unpublished reagents/analytic tools; T.O. analyzed data; P.L. and T.O. wrote the paper.

*S.S. and T.M. contributed equally to this work.

S. Shibata's present address: Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.

T. Miwa's present address: Department of Otolaryngology–Head and Neck Surgery, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.