FGFR1-Frs2/3 Signalling Maintains Sensory Progenitors during Inner Ear Hair Cell Formation

Kazuya Ono,Noriko Gotoh,Tomoko Kita,Marie Paschaki,Yoshiki Sasai,Kiyoshi Kawakami,Siu-Shan Mak,Raj K Ladher,Shigeru Sato,Paul O'Neill,Masataka Ito,Kathryn S E Cheah

doi:10.1371/journal.pgen.1004118

Abstract

Inner ear mechanosensory hair cells transduce sound and balance information. Auditory hair cells emerge from a Sox2-positive sensory patch in the inner ear epithelium, which is progressively restricted during development. This restriction depends on the action of signaling molecules. Fibroblast growth factor (FGF) signalling is important during sensory specification: attenuation of Fgfr1 disrupts cochlear hair cell formation; however, the underlying mechanisms remain unknown. Here we report that in the absence of FGFR1 signaling, the expression of Sox2 within the sensory patch is not maintained. Despite the down-regulation of the prosensory domain markers, p27Kip1, Hey2, and Hes5, progenitors can still exit the cell cycle to form the zone of non-proliferating cells (ZNPC), however the number of cells that form sensory cells is reduced. Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase. We suggest that FGF signaling, through the activation of MAP kinase, is necessary for the maintenance of sensory progenitors and commits precursors to sensory cell differentiation in the mammalian cochlea.

Highlights

The mammalian cochlea transduces sound using a dedicated sensory organ, the organ of Corti, which comprises of a highly ordered array of mechanosensory hair cells (HCs) and their associated support cells (SCs)
In this study we address an old problem: how do signals from the fibroblast growth factor (FGF) family control hair cell number? We used mice in which one of the receptors for FGF (Fgfr1) is mutated and found that the expression of a stem cell protein, Sox2 is not maintained
These findings suggest that it may be possible to amplify the number of hair cell progenitors in culture by tuning FGF activity, providing a route to replace damaged inner ear hair cells

Summary

Introduction

The mammalian cochlea transduces sound using a dedicated sensory organ, the organ of Corti, which comprises of a highly ordered array of mechanosensory hair cells (HCs) and their associated support cells (SCs). The arrangement of cochlear HCs, 3 rows of outer hair cells (OHCs) and one row of inner hair cells (IHCs), together with SCs results from a balance between specification, progenitor expansion and differentiation [1]. The first step in HC specification is the induction of a Sox2positive territory known as the sensory patch. BMP signalling [10] specifies the prosensory domain, the immediate precursors of the HCs and SCs, from within this Sox2positive sensory patch. The prosensory domain first becomes post-mitotic at the apical end of the cochlea from E12.5, spreading basally until E14.5 [11,12]

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