Fgf10 is required for specification of non-sensory regions of the cochlear epithelium

Abstract

The vertebrate inner ear is a morphologically complex sensory organ comprised of two compartments, the dorsal vestibular apparatus and the ventral cochlear duct, required for motion and sound detection, respectively. Fgf10, in addition to Fgf3, is necessary for the earliest stage of otic placode induction, but continued expression of Fgf10 in the developing otic epithelium, including the prosensory domain and later in Kolliker’s organ, suggests additional roles for this gene during morphogenesis of the labyrinth. While loss of Fgf10 was implicated previously in semicircular canal agenesis, we show that Fgf10−/+ embryos also exhibit a reduction or absence of the posterior semicircular canal, revealing a dosage-sensitive requirement for FGF10 in vestibular development. In addition, we show that Fgf10−/− embryos have previously unappreciated defects of cochlear morphogenesis, including a somewhat shortened duct, and, surprisingly, a substantially narrower duct. The mutant cochlear epithelium lacks Reissner’s membrane and a large portion of the outer sulcus--two non-contiguous, non-sensory domains. Marker gene analyses revealed effects on Reissner’s membrane as early as E12.5–E13.5 and on the outer sulcus by E15.5, stages when Fgf10 is expressed in close proximity to Fgfr2b, but these effects were not accompanied by changes in epithelial cell proliferation or death. These data indicate a dual role for Fgf10 in cochlear development: to regulate outgrowth of the duct and subsequently as a bidirectional signal that sequentially specifies Reissner’s membrane and outer sulcus non-sensory domains. These findings may help to explain the hearing loss sometimes observed in LADD syndrome subjects with FGF10 mutations.

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

“…The formation of Reissner’s membrane is dependent on Fgf10, which normally signals through Fgfr2-IIIb (Urness et al, 2015). This raises the question of how Reissner’s membrane might be expanded in Esrp1 −/− mutants given the near complete replacement of Fgfr2-IIIb with Fgfr2-IIIc, an isoform that does not respond to Fgf10 (Zhang et al, 2006).…”

“…Reissner’s membrane does not form in Fgf10 −/− embryos (Urness et al 2015). A similar phenotype might have been expected in Esrp1 −/− mutants given the aberrant splicing of Fgfr2 , which reduces the abundance of Fgfr2-IIIb, the high affinity Fgf10 receptor (Zhang et al, 2006).…”

Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates

“…It is likely that these short-range signals interact with and modify other patterning signals in the cochlear duct, such as FGF10 and FGF20 (Huh et al, 2012; Urness et al, 2015), although signals that promote specific cell fates in the outer hair cell region, such as outer hair cells and Deiters’ cells, remain to be identified. We do not know the nature of signals that limit the size of the organ of Corti on the abneural side of the cochlear duct, but given the proximity of a strong source of BMP4 in the future outer sulcus (Morsli et al, 1998; Ohyama et al, 2010), it is likely that this factor may play a role.…”

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

“…1A). This includes Bmp4, Fgf8, Fgf10, Fgf20 and Notch pathway components (Groves and Fekete, 2012;Hayashi et al, 2008b;Jacques et al, 2007;Ohyama et al, 2010;Urness et al, 2015). Transcripts for Wnt7b, Wnt7a and Wnt5a are asymmetrically and dynamically expressed within the prosensory domain of the cochlear duct as the OC begins to differentiate (Bohnenpoll et al, 2014;Dabdoub and Kelley, 2005;Qian et al, 2007).…”