Normal development of the peripheral auditory system requires coordinated deployment of signaling molecules to direct appropriate transcriptional responses in the myriad tissues that contribute to the ear. Fibroblast growth factors (FGFs) are among the important signals required for normal ear development and reductions in FGF signaling cause sensorineural and/or conductive hearing loss in several human syndromes. Over activation of FGF signaling is also detrimental. We found that loss of mouse DUSP6/MKP3, an ERK phosphatase that functions as a negative feedback regulator of FGF signaling, and is expressed in lineages giving rise to all three divisions of the ear, causes variably penetrant and expressive small size, craniosynostosis and conductive hearing loss. These phenotypes are similar to those caused by activating mutations in human FGFRs 1-3, but are unexplored from an auditory perspective in mouse models. To address the overall hypothesis that inappropriate activation of FGF signaling adversely affects development of the ear, we will use mouse genetics, gene and protein localization studies, audiometrics and skeletal analyses to determine the otic and other phenotypes of mice bearing combinations of Fgfr gain-of-function and Dusp6 null alleles and determine the unique and redundant roles of other ERK phosphatases in otic development. Our findings will help to focus attention on the likelihood that different activators and inhibitors of FGF signaling may currently be unrecognized as causal or modifying for various human hearing loss syndromes and that pharmacologic treatments aimed at targeted modulation of FGF signaling for amelioration of other FGFR-mediated conditions may have additional clinical applications for hearing loss prevention. Finally, a detailed understanding of the consequences of modulating FGF signaling is likely to be an important parameter in developing strategies for repair or regeneration of inner ear cell types.

Public Health Relevance

Hearing loss is the most common human sensory deficit and can be caused by mutations that change the levels of Fibroblast Growth Factor (FGF) signaling during development. We are using mice to model genetic cases of inappropriate activation of FGF signaling in order to understand the development of hearing loss in these conditions. These studies are expected to contribute knowledge that will be used in developing therapies for hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC002043-17
Application #
8265819
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1993-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
17
Fiscal Year
2012
Total Cost
$306,483
Indirect Cost
$102,840
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Lee, Pin-Hui; Lin, Hui-Chen; Huang, Angela Song-En et al. (2014) Diabetes and risk of tuberculosis relapse: nationwide nested case-control study. PLoS One 9:e92623
Mansour, Suzanne L; Twigg, Stephen R F; Freeland, Rowena M et al. (2009) Hearing loss in a mouse model of Muenke syndrome. Hum Mol Genet 18:43-50
Urness, Lisa D; Li, Chaoying; Wang, Xiaofen et al. (2008) Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development. Dev Dyn 237:163-9
Li, Chaoying; Scott, Daryl A; Hatch, Ekaterina et al. (2007) Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development 134:167-76
Yang, W; Li, C; Mansour, S L (2001) Impaired motor coordination in mice that lack punc. Mol Cell Biol 21:6031-43
Yang, W; Li, C; Ward, D M et al. (2000) Defective organellar membrane protein trafficking in Ap3b1-deficient cells. J Cell Sci 113 ( Pt 22):4077-86
Yang, W; Mansour, S L (1999) Expression and genetic analysis of prtb, a gene that encodes a highly conserved proline-rich protein expressed in the brain. Dev Dyn 215:108-16
Yang, W; Musci, T S; Mansour, S L (1997) Trapping genes expressed in the developing mouse inner ear. Hear Res 114:53-61