1 in 500 children are born with some degree of hearing loss. It is estimated that half these cases of hearing loss have a hereditary basis, some of which due to defects in the development of the inner ear. It is possible that an understanding of the earliest events in ear development may shed light on some causes of hereditary deafness. Our laboratory has chosen to study the earliest events in inner ear development - the transformation of embryonic ectoderm adjacent to the hindbrain into the otic placode, from which the entire inner ear and its associated neurons will ultimately derive. We have previously shown that signals from cranial mesoderm are necessary for otic placode induction, and that at least some of these signals are members of the Fibroblast Growth Factor (FGF) family. We have also shown that only some populations of cranial ectoderm are competent to respond to FGF signaling in this fashion, and that FGF responsiveness correlates with the expression of genes that mark the so-called """"""""pre-placodal"""""""" region adjacent to the anterior neural plate from which all craniofacial placodes will derive. Finally, we have shown that Wnt signaling appears to act on cells that have received FGF signaling, and directs them to an otic placode, rather than an epidermal fate. This renewal seeks to build on our previous results by asking how FGF and Wnt signaling activate otic placode genes, how ectoderm cells acquire the competence to respond to FGF signaling, and how transcriptional regulators mediate the choice between otic placode and epidermis.
In Specific Aim 1, we will determine whether FGF signaling induces the otic placode through the Ras/MAP kinase signaling pathway.
In Specific Aim 2, we will determine whether the competence to respond to FGF signaling in otic placode induction is regulated by the presence of a functional FGF signaling pathway, or by the expression of transcription factors such as Six1, Eya2, Dachl or FoxiS in pre-placodal ectoderm.
In Specific Aim 3 we will determine to what degree the Wnt and FGF signaling pathways act synergistically or independently during otic placode induction, and whether Wnt signaling directly represses epidermal fates. Finally, in Specific Aim 4, we will ask whether a novel forkhead family transcription factor, Foxi2, regulates the size of the otic placode by repressing induction of otic placode genes
|Birol, Onur; Ohyama, Takahiro; Edlund, Renée K et al. (2016) The mouse Foxi3 transcription factor is necessary for the development of posterior placodes. Dev Biol 409:139-51|
|Edlund, Renée K; Ohyama, Takahiro; Kantarci, Husniye et al. (2014) Foxi transcription factors promote pharyngeal arch development by regulating formation of FGF signaling centers. Dev Biol 390:1-13|
|Groves, Andrew K; LaBonne, Carole (2014) Setting appropriate boundaries: fate, patterning and competence at the neural plate border. Dev Biol 389:2-12|
|Khatri, Safia B; Edlund, Renée K; Groves, Andrew K (2014) Foxi3 is necessary for the induction of the chick otic placode in response to FGF signaling. Dev Biol 391:158-69|
|Yang, Lu; O'Neill, Paul; Martin, Kareen et al. (2013) Analysis of FGF-dependent and FGF-independent pathways in otic placode induction. PLoS One 8:e55011|
|Khatri, Safia B; Groves, Andrew K (2013) Expression of the Foxi2 and Foxi3 transcription factors during development of chicken sensory placodes and pharyngeal arches. Gene Expr Patterns 13:38-42|
|Basch, Martín L; Ohyama, Takahiro; Segil, Neil et al. (2011) Canonical Notch signaling is not necessary for prosensory induction in the mouse cochlea: insights from a conditional mutant of RBPjkappa. J Neurosci 31:8046-58|
|Jayasena, Chathurani S; Ohyama, Takahiro; Segil, Neil et al. (2008) Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development 135:2251-61|
|Ohyama, Takahiro; Mohamed, Othman A; Taketo, Makoto M et al. (2006) Wnt signals mediate a fate decision between otic placode and epidermis. Development 133:865-75|
|Martin, Kareen; Groves, Andrew K (2006) Competence of cranial ectoderm to respond to Fgf signaling suggests a two-step model of otic placode induction. Development 133:877-87|
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