Sung-Ho Huh¹, Jennifer Jones², Mark E. Warchol², David M. Ornitz^1,*

¹ Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, United States of America

^*To whom correspondence may be addressed.

Abstract
A large proportion of age-related hearing loss is caused by loss or damage to outer hair cells in the organ of Corti. The organ of Corti is the mechanosensory transducing apparatus in the inner ear and is composed of inner hair cells, outer hair cells, and highly specialized supporting cells. The mechanisms that regulate differentiation of inner and outer hair cells are not known. Here we report that fibroblast growth factor 20 (FGF20) is required for differentiation of cells in the lateral cochlear compartment (outer hair and supporting cells) within the organ of Corti during a specific developmental time. In the absence of FGF20, mice are deaf and lateral compartment cells remain undifferentiated, postmitotic, and unresponsive to Notch-dependent lateral inhibition. These studies identify developmentally distinct medial (inner hair and supporting cells) and lateral compartments in the developing organ of Corti. The viability and hearing loss in Fgf20 knockout mice suggest that FGF20 may also be a deafness-associated gene in humans.

Author Summary
A large proportion of age-related hearing loss is caused by loss or damage to outer hair cells in the organ of Corti. The organ of Corti is a highly specialized structure in the inner ear that is composed of inner hair cells, outer hair cells, and associated supporting cells. Although we understand some of the mechanisms that regulate hair cell versus supporting cell differentiation, the mechanisms that regulate differentiation of inner versus outer hair cells are not known. One potential candidate is fibroblast growth factor (FGF) signaling, which is known to regulate the morphogenesis of many sensory organs, including the organ of Corti. In this study, we find that FGF20 signaling is required at a specific time during development to initiate differentiation of cells in the mouse lateral cochlear compartment (which contains outer hair cells and supporting cells, but not inner hair cells). In the absence of FGF20, mice are deaf, and lateral compartment cells remain undifferentiated and unresponsive to mechanisms that regulate the final stages of differentiation. These findings are significant given the importance of outer hair cells during age-related hearing loss. Our studies also suggest that genetic mutations in FGF20 may result in deafness in humans and that FGF20 may be an important factor for the repair or regeneration of sensory cells in the inner ear.

Citation: Huh S-H, Jones J, Warchol ME, Ornitz DM (2012) Differentiation of the Lateral Compartment of the Cochlea Requires a Temporally Restricted FGF20 Signal. PLoS Biol 10(1): e1001231. doi:10.1371/journal.pbio.1001231

Academic Editor: Andy Groves, Baylor College of Medicine, United States of America

Received: June 18, 2011; Accepted: November 18, 2011; Published: January 3, 2012

Copyright: ⓒ 2012 Huh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was funded by the Department of Developmental Biology, the Hearing Health Foundation (SH), Action on Hearing Loss, contributions from Edward and Linda Ornitz, NIDCD grant DC006283 (MEW) and NIH support grants (P30DC04665, P30DK052574, and P30AR057235). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ABR, auditory brainstem response; βGal, β-galactosidase; DCs, Deiters' cells; FGF, fibroblast growth factor; FGFR, FGF receptor; HC, hair cell; HeCs, Hensen's cells; IHC, inner hair cell; IPC, inner pillar cell; IPhC, inner phalangeal cells; OC, organ of Corti; OHC, outer hair cell; OPC, outer pillar cell; PCs, pillar cells; SC, supporting cell