Early and transient requirements for FGFR2b/1b ligands in cochlear sensory and neural cell subtype differentiation

Abstract

We probed the roles of FGFR2b/1b signaling in mid-gestation cochlear development by inducing dnFGFR2b, a ligand trap that sequesters FGF3 and FGF10. Analyses following E11.5-E18.5 induction showed that FGFR2b/1b ligands are required for normal hair cell numbers, to repress inner hair cell differentiation in the lateral organ of Corti and to promote outer hair cell differentiation. FGFR2b/1b ligands also repress outer support cell numbers and promote differentiation of outer pillar cells and Deiters' cells. Finally, these ligands also promote normal cochlear ganglion size and morphology as well as differentiation of CALB2-positive spiral ganglion neuronal subtypes. Delaying the start of dnFGFR2b expression to successive days after E11.5 revealed a critical period of E11.5-E13.5 for FGFR2b/1b signaling in sensory development and of E11.5-E14.5 in ganglion development. Strikingly, even transient induction of dnFGFR2b from E11.5-E12.5 was sufficient to largely recapitulate the phenotypes seen following long-term induction, suggesting that some of the key FGFR2b/1b ligand-dependent events controlling cochlear cell subtype differentiation occur long before such differentiation is evident, and suggesting a new window within which to search for regulators of cochlear differentiation.