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

• DOI: 10.1371/journal.pgen.1004118
• Publication Date: 2014-01-23T23:13:08Z
• Authors: Kazuya Ono; Tomoko Kita; Shigeru Sato; Paul O'Neill; Siu-Shan Mak; Marie Paschaki; Masataka Ito; Noriko Gotoh; Kiyoshi Kawakami; Yoshiki Sasai; Raj K. Ladher
• Keywords: 0303 health sciences; Hair Cells, Auditory, Inner; SOXB1 Transcription Factors; Cell Cycle; Gene Expression Regulation, Developmental; Membrane Proteins; Cell Differentiation; QH426-470; Epithelium; Cochlea; 03 medical and health sciences; Ear, Inner; Genetics; Animals; Receptor, Fibroblast Growth Factor, Type 1; Research Article; Adaptor Proteins, Signal Transducing; Protein Binding; Signal Transduction

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, p27(Kip1), 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.