Canonical Wnt signaling regulates the proliferative expansion and differentiation of fibrocytes in the murine inner ear

Abstract

Otic fibrocytes tether the cochlear duct to the surrounding otic capsule but are also critically involved in maintenance of ion homeostasis in the cochlea, thus, perception of sound. The molecular pathways that regulate the development of this heterogenous group of cells from mesenchymal precursors are poorly understood. Here, we identified epithelial Wnt7a and Wnt7b as possible ligands of Fzd-mediated β-catenin (Ctnnb1)-dependent (canonical) Wnt signaling in the adjacent undifferentiated periotic mesenchyme (POM). Mice with a conditional deletion of Ctnnb1 in the POM exhibited a complete failure of fibrocyte differentiation, a severe reduction of mesenchymal cells surrounding the cochlear duct, loss of pericochlear spaces, a thickening and partial loss of the bony capsule and a secondary disturbance of cochlear duct coiling shortly before birth. Analysis at earlier stages revealed that radial patterning of the POM in two domains with highly condensed cartilaginous precursors and more loosely arranged inner mesenchymal cells occurred normally but that proliferation in the inner domain was reduced and cytodifferentiation failed. Cells with mis/overexpression of a stabilized form of Ctnnb1 in the entire POM mesenchyme sorted to the inner mesenchymal compartment and exhibited increased proliferation. Our analysis suggests that Wnt signals from the cochlear duct epithelium are crucial to induce differentiation and expansion of fibrocyte precursor cells. Our findings emphasize the importance of epithelial-mesenchymal signaling in inner ear development.

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

“…In our studies, the developing reaction was stopped based on the strongest expression at any of the three time points, such that Wnt7a appeared to be absent at E12.5. However, slides developed for longer confirmed low-level expression of Wnt7a at E12.5 (data not shown), as previously shown (Bohnenpoll et al, 2014).…”

“…The onset of Wnt5a was later than of Wnt7b and was not detected in the sensory domain of the E12.5 cochlea (Fig. S4C) (Bohnenpoll et al, 2014). Wnt5a was first detected at E13.5 in the medial domain, marked by Jag1 (Fig.…”

“…We performed a developmental time series for Wnt transcripts to fill in sampling gaps between E12.5 and E15.5 (Fig. S4) to complement previous studies (Bohnenpoll et al, 2014;Dabdoub and Kelley, 2005;Qian et al, 2007).…”

“…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). Such diversity suggests multiple roles for Wnt signaling that vary as cochlear development progresses (Munnamalai and Fekete, 2013).…”

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice

“…Wdr1 (WD40 repeat domain) shows noise-modulated expression in both organ of Corti and lateral wall (Oh et al 2002), and has been proposed to serve a protective role. Several genes in the region (Fzd1, Shh, Hmx1, Otop1) appear in the cochlear literature primarily for their role in development (Riccomagno et al 2002;Wang and Lufkin 2005;Hughes et al 2006;Bohnenpoll et al 2014), yet may participate in responses to stress. If allelic similarity between B6, BALB, and CBA/J can serve as a guide, we may particularly suspect genes that are similar between BALB and CBA/J, yet polymorphic between these strains and B6.…”