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Abstract
ABSTRACTDuring embryonic development, the otic epithelium and surrounding periotic mesenchymal cells originate from distinct lineages and coordinate to form the mammalian cochlea. Epithelial sensory precursors within the cochlear duct first undergo terminal mitosis before differentiating into sensory and non-sensory cells. In parallel, periotic mesenchymal cells differentiate to shape the lateral wall, modiolus and pericochlear spaces. Previously, Wnt activation was shown to promote proliferation and differentiation of both otic epithelial and mesenchymal cells. Here, we fate-mapped Wnt-responsive epithelial and mesenchymal cells in mice and found that Wnt activation resulted in opposing cell fates. In the post-mitotic cochlear epithelium, Wnt activation via β-catenin stabilization induced clusters of proliferative cells that dedifferentiated and lost epithelial characteristics. In contrast, Wnt-activated periotic mesenchyme formed ectopic pericochlear spaces and cell clusters showing a loss of mesenchymal and gain of epithelial features. Finally, clonal analyses via multi-colored fate-mapping showed that Wnt-activated epithelial cells proliferated and formed clonal colonies, whereas Wnt-activated mesenchymal cells assembled as aggregates of mitotically quiescent cells. Together, we show that Wnt activation drives transition between epithelial and mesenchymal states in a cell type-dependent manner.
Highlights
Development of the embryo requires multiple rounds of transition between epithelial and mesenchymal states, coined epithelialmesenchymal or mesenchymal-epithelial transitions (EMT and MET, respectively) (Hay, 1995; Thiery and Sleeman, 2006)
In Lgr5-tdTomato-Ctnnb1 foci, we found a marked decrease in epithelial markers (E-cadherin, keratin 8 (Krt8), Sox2) and an increase in proliferation (Ki67) and mesenchymal markers (Fig. S5B-I), confirming that the observed phenotype is a result of β-catenin stabilization in epithelial cells
The cochlear epithelium deriving from the otic placode contains prosensory cells and gives rise to sensory and non-sensory cells in the organ of Corti (Driver et al, 2013; Ohyama and Groves, 2004)
Summary
Development of the embryo requires multiple rounds of transition between epithelial and mesenchymal states, coined epithelialmesenchymal or mesenchymal-epithelial transitions (EMT and MET, respectively) (Hay, 1995; Thiery and Sleeman, 2006). EMT is characterized by a loss of adhesion molecules and adoption of migratory behavior, whereas MET features apical-basal polarization and formation of junctional complexes, as well as the loss of cell mobility, proliferation and expression of myriad mesenchymal markers (Thiery et al, 2009). Handling Editor: Patrick Tam Received 30 November 2020; Accepted 5 May 2021 neural crest cells deriving from the neuroepithelium undergo EMT to become migratory mesenchymal cells, which contribute to diverse organ systems such as the cardiovascular organs, skin pigment cells, craniofacial skeleton and the peripheral nervous systems including the inner ear (Freyer et al, 2011; Martik and Bronner, 2017; Noden, 1983; Piacentino et al, 2020)
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