Notch Prosensory Effects in the Mammalian Cochlea Are Partially Mediated by Fgf20

Abstract

Hearing loss is becoming an increasingly prevalent problem affecting more than 250 million people worldwide. During development, fibroblast growth factors (FGFs) are required for inner ear development as well as hair cell formation in the mammalian cochlea and thus make attractive therapeutic candidates for the regeneration of sensory cells. Previous findings showed that Fgfr1 conditional knock out mice exhibited hair cell and support cell formation defects. Immunoblocking with Fgf20 antibody in vitro produced a similar phenotype. While hair cell differentiation in mice starts at embryonic day (E)14.5, beginning with the inner hair cells, Fgf20 expression precedes hair cell differentiation at E13.5 in the cochlea. This suggests a potential role for Fgf20 in priming the sensory epithelium for hair cell formation. Treatment of explants with a gamma-secretase inhibitor, DAPT, decreased Fgf20 mRNA, suggesting that Notch is upstream of Fgf20. Notch signaling also plays an early role in prosensory formation during cochlear development. In this report we show that during development, Notch-mediated regulation of prosensory formation in the cochlea occurs via Fgf20. Addition of exogenous FGF20 compensated for the block in Notch signaling and rescued Sox2, a prosensory marker, and Gfi1, an early hair cell marker in explant cultures. We hypothesized that Fgf20 plays a role in specification, amplification, or maintenance of Sox2 expression in prosensory progenitors of the developing mammalian cochlea.

Jag1b is essential for patterning inner ear sensory cristae by regulating anterior morphogenetic tissue separation and preventing posterior cell death

“…We also found that Jag1b is required for fgf10a expression, suggesting Fgf10a may be a signal that mediates cell survival of posterior prosensory patches. In agreement with our finding, a previous study indicated that Notch functions upstream of Fgf20 and Notch-mediated regulation of prosensory formation in the cochlea occurs via Fgf20 (Munnamalai et al, 2012). In addition, Fgf10 expression was also reduced in the inner ear of RBPj CKO mice (Yamamoto et al, 2011).…”

Notch-Wnt-Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner

“…Instead, DAPT inhibited prosensory formation. Prosensory inhibition due to DAPT treatment occurs comparably early (E12.5) and typically requires a higher dose of DAPT (30 µM) (Munnamalai et al, 2012; as compared with Fig. 5E).…”

Sensory hair cell development and regeneration: similarities and differences

“…Second, conditional deletion of Jag1 leads to the downregulation of this prosensory marker, resulting in a malformed cochlear duct that contains few hair cells and supporting cells (Brooker et al, 2006;Kiernan et al, 2006). Third, cultured explants exposed to Notch inhibitors fail to form a prosensory domain (Munnamalai et al, 2012). Conversely, gain-of-function studies using virus-mediated overexpression of NICD in the chick cochlear duct (Daudet and Lewis, 2005) or transgenic approaches in the mouse inner ear (Hartman et al, 2010;Liu et al, 2012b;Pan et al, 2013) result in ectopic sensory patches composed of hair cells and supporting cells.…”

“…Two independent studies pinpointed FGF20 as the candidate ligand for FGFR1 in the cochlea, with both FGF20 and FGFR1 being required for the development of at least a subset of hair cells and supporting cells (Hayashi et al, 2008;Huh et al, 2012). The prosensory effect of FGF20 was further shown to act downstream of Notch signaling; FGF20 treatment rescues prosensory specification that is impeded by Notch inhibition (Munnamalai et al, 2012). Remarkably, deletion of Fgf20 did not lead to vestibular dysfunction, suggesting that the role of FGF20 in hair cell specification might be specific to the cochlea.…”

“…The availability of genetic tools has enabled us to further dissect components of these pathways. Moreover, these studies have begun to reveal the complex interplay that exists among different pathways at different developmental stages, ranging from otic placode specification (Jayasena et al, 2008) and sensory cell specification (Benito-Gonzalez and Doetzlhofer, 2014;Bok et al, 2013;Munnamalai et al, 2012;Tateya et al, 2013) to the maintenance of cell fate (Doetzlhofer et al, 2009;Li et al, 2015). As insights into the roles of additional pathways in these diverse contexts culminate (e.g.…”