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WIREs Dev Biol
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Hearing crosstalk: the molecular conversation orchestrating inner ear dorsoventral patterning

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The inner ear is a structurally and functionally complex organ that functions in balance and hearing. It originates during neurulation as a localized thickened region of rostral ectoderm termed the otic placode, which lies adjacent to the developing caudal hindbrain. Shortly after the otic placode forms, it invaginates to delineate the otic cup, which quickly pinches off of the surface ectoderm to form a hollow spherical vesicle called the otocyst; the latter gives rise dorsally to inner ear vestibular components and ventrally to its auditory component. Morphogenesis of the otocyst is regulated by secreted proteins, such as WNTs, BMPs, and SHH, which determine its dorsoventral polarity to define vestibular and cochlear structures and sensory and nonsensory cell fates. In this review, we focus on the crosstalk that occurs among three families of secreted molecules to progressively polarize and pattern the developing otocyst.

Diagram of the secreted growth factors that pattern the otocyst. Two factors are known to act primarily on the dorsal otocyst during its early patterning. WNTs, secreted by the roof plate of the neural tube, act on the dorsomedial region of the otocyst, and BMPs, similarly secreted by the roof plate, but perhaps also by the cristae of the developing otocyst (not shown), act on the dorsolateral region of the otocyst. By contrast, SHH, secreted by the floor plate of neural tube and the notochord, acts primarily on the ventral otocyst. Crosstalk occurs among these three signaling molecules to orchestrate dorsoventral patterning of the otocyst.
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Summary of the known otocyst transcription factors regulated by crosstalk among three families of secreted proteins during dorsoventral (DV) patterning. DV patterning of the otocyst is orchestrated through crosstalk among three families of secreted proteins that regulate the expression of transcription factors in a temporospatial manner. BMP signaling, which is required for the development of the dorsal (vestibular) component of the inner ear, upregulates the expression of two transcription factors, Dlx5 and Hmx3, both of which are essential for vestibular development. WNT and BMP signaling partner to induce Dlx5 expression in the dorsolateral wall of the otocyst, whereas WNT signaling acts alone in the dorsomedial wall to regulate the expression of Gbx2, which in turn seems to be required for Dlx5 expression. SHH signaling, which is required for the development of the ventral (cochlear) component of the inner ear, upregulates the expression of two transcription factors, Pax2 and Otx2, both of which are essential for cochlear development. The expression of transcription factors in the dorsal and ventral otocyst also is inhibited by secreted factors, with BMP signaling downregulating Otx2 expression and SHH signaling downregulating Hmx3 expression and arguably downregulating Dlx5 expression.
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Diagram showing how integrated BMP and SHH signaling contributes to dorsoventral (DV) patterning of the otocyst. Owing to their sites of expression in the embryo and their limited diffusion in the head mesenchyme, BMP ligands act mainly on the dorsal otocyst and SHH ligands act mainly on the ventral otocyst. BMP signaling activates PKA in the dorsal otocyst, while SHH inhibits it in the ventral otocyst, establishing a dorsal‐high to ventral‐low gradient of PKA activity. Activated PKA phosphorylates GLI3FL, partially processing it to form GLI3R; in contrast, in the absence of activated PKA, GLI3A is not proteolytically processed. Thus, a dorsal‐high to ventral‐low gradient in the ratio of GLI3R/GLI3A spans the DV axis of the otocyst. Dorsally, GLI3R activates transcription of the BMP target gene, Hmx3. Ventrally, GLI3A activates transcription of the SHH target genes, Pax2 and Otx2.
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Diagram of the regional expression patterns of transcription factors in dorsal and ventral regions of the early otocyst. Dlx5 and Gbx2 are expressed in the dorsomedial otocyst in response to WNT signaling. Hmx3 is expressed in the dorsolateral otocyst in response to BMP signaling; its expression domain overlaps that of dorsolaterally expressed Dlx5, which requires both WNT and BMP signaling. Pax2 is expressed in the ventromedial otocyst and Otx2 is expressed in the ventrolateral otocyst, both in response to SHH signaling.
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Signaling Pathways > Cell Fate Signaling
Vertebrate Organogenesis > From a Tubular Primordium: Non-Branched
Establishment of Spatial and Temporal Patterns > Gradients