Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates.

Abstract	The stereotyped arrangement of cochlear sensory and supporting cells is critical for auditory function. Our previous studies showed that Muenke syndrome model mice (Fgfr3P244R/+) have hearing loss associated with a supporting cell fate transformation of two Deiters' cells to two pillar cells. We investigated the developmental origins of this transformation and found that two prospective Deiters' cells switch to an outer pillar cell-like fate sequentially between embryonic day 17.5 (E17.5) and postnatal day 3 (P3). Unexpectedly, the Fgfr3P244R/+ hearing loss and supporting cell fate transformation are not rescued by genetically reducing fibroblast growth factor 8 (FGF8), the FGF receptor 3c (FGFR3c) ligand required for pillar cell differentiation. Rather, reducing FGF10, which normally activates FGFR2b or FGFR1b, is sufficient for rescue of cochlear form and function. Accordingly, we found that the P244R mutation changes the specificity of FGFR3b and FGFR3c such that both acquire responsiveness to FGF10. Moreover, Fgf10 heterozygosity does not block the Fgfr3P244R/+ supporting cell fate transformation but instead allows a gradual reversion of fate-switched cells toward the normal phenotype between P5 and at least P14. This study indicates that Deiters' and pillar cells can reversibly switch fates in an FGF-dependent manner over a prolonged period of time. This property might be exploited for the regulation of sensory cell regeneration from support cells.
Authors	Suzanne L Mansour, Chaoying Li, Lisa D Urness
Journal	Genes & development (Genes Dev) Vol. 27 Issue 21 Pg. 2320-31 (Nov 01 2013) ISSN: 1549-5477 [Electronic] United States
PMID	24145799 (Publication Type: Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural)
Chemical References	Fibroblast Growth Factors
Topics	Animals Cell Differentiation Cochlea (cytology, embryology, metabolism) Craniosynostoses (complications, embryology, genetics) Disease Models, Animal Fibroblast Growth Factors (genetics, metabolism) Gene Dosage Hair Cells, Auditory (cytology) Hearing Loss (embryology, etiology, genetics) Mice Signal Transduction

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