FGFR1 Is Required for the Development of the Auditory Sensory Epithelium

Abstract

The mammalian auditory sensory epithelium, the organ of Corti, comprises the hair cells and supporting cells that are pivotal for hearing function. The origin and development of their precursors are poorly understood. Here we show that loss-of-function mutations in mouse fibroblast growth factor receptor 1 (Fgfr1) cause a dose-dependent disruption of the organ of Corti. Full inactivation of Fgfr1 in the inner ear epithelium by Foxg1-Cre-mediated deletion leads to an 85% reduction in the number of auditory hair cells. The primary cause appears to be reduced precursor cell proliferation in the early cochlear duct. Thus, during development, FGFR1 is required for the generation of the precursor pool, which gives rise to the auditory sensory epithelium. Our data also suggest that FGFR1 might have a distinct later role in intercellular signaling within the differentiating auditory sensory epithelium.

Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti

“…Previous reports have described the expression of both Fgfr3 and Fgf8 in the developing cochlea by in situ hybridization and immunohistochemistry (Pirvola et al, 1995(Pirvola et al, , 2002Shim et al, 2005). Our own in situ analysis confirms and extends these early reports ( Fig.…”

“…This model (Fig. 9) of excess of FGFR1 activation leading to extra outer hair cells fits with the dramatic reduction in outer hair cells described by Pirvola and colleagues when Fgfr1 is knocked out in the developing inner ear (Pirvola et al, 2002). These authors suggested that FGFR1 regulates the numbers of hair cells and support cells that are formed in a dose-dependent manner (Pirvola et al, 2002).…”

“…At early stages of embryogenesis, Fgfr1, Fgfr2, and several FGFs, including FGF3, FGF8, FGF10, and FGF19, are critical for either the induction of the otic vesicle or the initial development of the sensory epithelium (Mansour et al, 1993;Ladher et al, 2000Ladher et al, , 2005Pirvola et al, 2000Pirvola et al, , 2002Phillips et al, 2001Phillips et al, , 2004Pauley et al, 2003;. At intermediate stages of development, FGF signaling is also important; tissuespecific deletion of Fgfr1 results in severe defects in the development of the auditory sensory epithelium apparently due to a severe reduction in the precursor cells that give rise to the organ of Corti.…”

“…At intermediate stages of development, FGF signaling is also important; tissuespecific deletion of Fgfr1 results in severe defects in the development of the auditory sensory epithelium apparently due to a severe reduction in the precursor cells that give rise to the organ of Corti. In addition, Fgfr1 Ϫ/Ϫ mice show a selective loss of the OHCs and an increase in the number of cells that differentiate as pillar cells (Pirvola et al, 2002). At late stages of cochlear development, Fgfr3 is necessary for the development of the tunnel of Corti (Colvin et al, 1996).…”

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

“…For instance in proliferating brain stem cells FGFR1 is cytoplasmic whereas in differentiating neural cells FGFR1 accumulates in the cell nucleus (Stachowiak et al, 2012a). In agreement with this dual distribution, brain‐targeted FGFR1 knockout impairs both the cell proliferation and differentiation (Pirvola et al, 2002; Ohkubo et al, 2004) which may reflect the loss of FGFR1 signaling at the cell surface and the INFS, respectively (Stachowiak et al, 2012b). …”