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The mammalian cochlea is composed of sensory hair cells as well as multiple different types of non-sensory supporting cells. Pillar cells are one type of supporting cell that form the tunnel of Corti and include two morphologically and functionally distinct subtypes: inner pillar cells (IPCs) and outer pillar cells (OPCs). The processes of specification and differentiation of inner versus outer pillar cells are still unclear. Here, we show that β-Catenin is required for establishing IPC identity in the mammalian cochlea. To differentiate the transcriptional and adhesion roles of β-Catenin in establishing IPC identity, we examined two different models of β-Catenin deletion; one that deletes both transcriptional and structural functions and one which retains cell adhesion function but lacks transcriptional function. Here, we show that cochleae lacking β-Catenin transcriptional function lost IPCs and displayed extranumerary OPCs, indicating its requirement for establishing IPC identity. Overexpression of β-Catenin induced proliferation within IPCs but not ectopic IPCs. Single-cell transcriptomes of supporting cells lacking β-Catenin transcriptional function show a loss of the IPC and gain of OPC signatures. Finally, targeted deletion of β-Catenin in IPCs also led to the loss of IPC identity, indicating a cell autonomous role of β-Catenin in establishing IPC identity. As IPCs have the capacity to regenerate sensory hair cells in the postnatal cochlea, our results will aid in future IPC-based hair cell regeneration strategies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ebeid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mammalian cochlear development encompasses a series of morphological and molecular events that results in the formation of a highly intricate structure responsible for hearing. One remarkable event occurs during development is the cochlear lengthening that starts with cochlear outgrowth around E11 and continues throughout development. Different mechanisms contribute to this process including cochlear progenitor proliferation and convergent extension. We previously identified that FGF9 and FGF20 promote cochlear lengthening by regulating auditory sensory epithelial proliferation through FGFR1 and FGFR2 in the periotic mesenchyme. Here, we provide evidence that ETS-domain transcription factors ETV4 and ETV5 are downstream of mesenchymal FGF signaling to control cochlear lengthening. Next generation RNA sequencing identified that Etv1, Etv4 and Etv5 mRNAs are decreased in the Fgf9 and Fgf20 double mutant periotic mesenchyme. Deleting both Etv4 and Etv5 in periotic mesenchyme resulted in shortening of cochlear length but maintaining normal patterning of organ of Corti and density of hair cells and supporting cells. This recapitulates phenotype of mesenchymal-specific Fgfr1 and Fgfr2 deleted inner ear. Furthermore, analysis of Etv1/4/5 triple conditional mutants revealed that ETV1 does not contribute in this process. Our study reveals that ETV4 and ETV5 function downstream of mesenchymal FGF signaling to promote cochlear lengthening., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Development of multicellular organs requires the coordination of cell differentiation and patterning. Critical for sound detection, the mammalian organ of Corti contains functional units arranged tonotopically along the cochlear turns. Each unit consists of sensory hair cells intercalated by nonsensory supporting cells, both specified and radially patterned with exquisite precision during embryonic development. However, how cell identity and radial patterning are jointly controlled is poorly understood. Here we show that β-catenin is required for specification of hair cell and supporting cell subtypes and radial patterning of the cochlea in vivo. In 2 mouse models of conditional β-catenin deletion, early specification of Myosin7-expressing hair cells and Prox1-positive supporting cells was preserved. While β-catenin-deficient cochleae expressed FGF8 and FGFR3, both of which are essential for pillar cell specification, the radial patterning of organ of Corti was disrupted, revealed by aberrant expression of cadherins and the pillar cell markers P75 and Lgr6. Moreover, β-catenin ablation caused duplication of FGF8-positive inner hair cells and reduction of outer hair cells without affecting the overall hair cell density. In contrast, in another transgenic model with suppressed transcriptional activity of β-catenin but preserved cell adhesion function, both specification and radial patterning of the organ of Corti were intact. Our study reveals specific functions of β-catenin in governing cell identity and patterning mediated through cell adhesion in the developing cochlea., Competing Interests: The authors declare no competing interest.

Mammalian inner ear comprises of six sensory organs; cochlea, utricle, saccule, and three semicircular canals. The cochlea contains sensory epithelium known as the organ of Corti which senses sound through mechanosensory hair cells. Mammalian inner ear undergoes series of morphogenesis during development beginning thickening of ectoderm nearby hindbrain. These events require tight regulation of multiple signaling cascades including FGF, Wnt, Notch and Bmp signaling. In this review, we will discuss the role of newly emerging signaling, FGF signaling, for its roles required for cochlear development. [BMB Reports 2017; 50(10): 487-495].

The sensory and supporting cells (SCs) of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and SCs, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea.

A large proportion of age-related hearing loss is caused by loss or damage to outer hair cells in the organ of Corti. The organ of Corti is the mechanosensory transducing apparatus in the inner ear and is composed of inner hair cells, outer hair cells, and highly specialized supporting cells. The mechanisms that regulate differentiation of inner and outer hair cells are not known. Here we report that fibroblast growth factor 20 (FGF20) is required for differentiation of cells in the lateral cochlear compartment (outer hair and supporting cells) within the organ of Corti during a specific developmental time. In the absence of FGF20, mice are deaf and lateral compartment cells remain undifferentiated, postmitotic, and unresponsive to Notch-dependent lateral inhibition. These studies identify developmentally distinct medial (inner hair and supporting cells) and lateral compartments in the developing organ of Corti. The viability and hearing loss in Fgf20 knockout mice suggest that FGF20 may also be a deafness-associated gene in humans., Competing Interests: The authors have declared that no competing interests exist.

The mouse organ of Corti, housed inside the cochlea, contains hair cells and supporting cells that transduce sound into electrical signals. These cells develop in two main steps: progenitor specification followed by differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, Fgf20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and Fgf20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and Fgf20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the cochlea. To explain this genetic interaction and its effects on the basal end of the cochlea, we provide evidence that decreased Sox2 expression delays specification, which begins at the apex of the cochlea and progresses towards the base, while Fgf20-deletion results in premature onset of differentiation, which begins near the base of the cochlea and progresses towards the apex. Thereby, Sox2 and Fgf20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea. [ABSTRACT FROM AUTHOR]