How is the Inner Ear Induced?

The entire inner ear and the neurons that innervate it derive from a simple piece of embryonic ectoderm next to the hindbrain called the otic placode. This ectoderm thickens, invaginates and folds up to form the otocyst, which then grows and is sculpted to form the mature inner ear. The signals that induce the otic placode are produced by the hindbrain and the mesoderm underlying the placode. Work from a number of labs including our own suggests that members of the fibroblast growth factor (FGF) family are the primary inducing signals in otic placode induction, in collaboration with Wnt signaling.

It has been known for many years that all cranial sensory tissue – olfactory epithelium, the lens of the eye, the otic placode and the neurogenic trigeminal and epibranchial placodes – all derive from a common region of “pre-placodal” epithelium that lies adjacent to the anterior neural plate. A number of transcription factors are expressed in the pre-placodal domain, and we are characterizing one, a Forkhead family transcription factor called Foxi3. Strikingly, null mutants of Foxi3 no inner ear at all and completely fail to initiate the inner ear program from its earliest stages. We’ve shown that the ectoderm in these mice continues to receive inducing FGF signals, but in the absence of Foxi3, the tissue is not competent to initiate the ear program. We speculate that Foxi3 may act as a pioneer factor – it is expressed prior to inner ear induction but is necessary to organize chromatin into a transcriptionally competent state to interpret FGF signals. To test this, we have established a mouse ES cell model of otic placode induction, and have used CRISPR to generate Foxi3 mutant cells, cells expressing epitope tagged Foxi3 and a variety of ES cell lines expressing various fluorescent reporters for genes expressed in the pre-placodal to otic placode steps. We are now performing RNA-seq, ATAC-seq and ChIP-seq on these various cell lines to understand Foxi3’s role in ear induction.

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Yang, L., O’Neill, P., Martin, K., Maass, J.C., Vassilev, V., Ladher, R. and Groves, A.K. (2013). Analysis of FGF-dependent and FGF-independent pathways in otic placode induction. PLoS One 8, e55011.

Khatri, S.B. and Groves, A.K. (2013). Expression of Foxi2 and Foxi3 transcription factors during development of chicken sensory placodes and pharyngeal arches. Gene Expression Patterns 13, 38-42.

Jayasena, C.S., Ohyama, T., Segil, N. and Groves, A.K. (2008). Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development 135, 2251-2261.

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Ohyama, T., Mohamed, O.A., Taketo, M.M., Dufort, D. and Groves, A.K. (2006). Wnt signals mediate a fate decision between otic placode and epidermis. Development 133, 865-875.

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