We propose to elucidate mechanisms of development and regeneration in the inner ear in the zebrafish, Danio rerio. The inner ear arises form a simple thickening on the surface of the embryo termed the otic placode, which subsequently forms the otic vesicle where sensory epithelia and neurons of the ear arise. We have shown that each of these processes requires the cell signaling molecule Fgf. Additionally, various transcription factors belonging to the Pax2/5/8 and Sox2/3 families modify the response to Fgf to help establish different kinds of cell types. In three specific aims we will investigate how thee genes work during development, as well as during regeneration to repair damage that might otherwise cause deafness. 1) We will study how the related factors Sox2 and Sox3 regulate early development of the inner ear. We hypothesize that they initially work together to establish the otic placode. Soon thereafter, Sox2 promotes development of sensory epithelia and Sox3 promotes development of neurons that transmit signals from the ear to the brain. These studies will rely on transgenic lines in which Sox2 or Sox3, or other factors of interest, can be overexpressed by simply incubating embryos at elevated temperatures. 2) We will study how Fgf, Pax2/5 and Sox2 function in the maintenance and regeneration of sensory hair cells. These factors are known to regulate initial development, but we will now use a new technology (""""""""photo-MOs"""""""") that permit analysis of later functions. For example, we will block gene function after hair cells have formed to determine whether the gene is needed for hair cell survival;and after killing hair cells with a laser, we will determine whether these genes are necessary for regeneration. 3) We will investigate the role of the transcription factor Tfap2a in formation of neurons. Tfap2a has not previously been studied in the inner ear in any species, but we have discovered it has a profound stimulatory effect on neuron production in zebra fish. We will investigate how Tfap2a works, and how it interacts with the other factors known to promote neuron formation, such as Fgf and Sox3. Together, these studies will provide fundamental insights into mechanisms of otic placode induction and sensory/neural development. Because developmental mechanisms are broadly conserved, studying how these genes work in zebra fish could suggest candidates for """"""""gene therapy"""""""" to restore hearing in mammals.

Public Health Relevance

Loss of hearing is a common affliction and results from permanent loss of sensory hair cells and/or neurons of the inner ear. It is widely believed that it may be possible to restore hearing in humans using gene therapy to activate genes found to regulate the development or regeneration of sensory hair cells or neurons in other species. Using zebra fish as a model, we are investigating the functions of genes believed to regulate these processes in all vertebrates.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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Texas A&M University
Schools of Arts and Sciences
College Station
United States
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Gou, Yunzi; Vemaraju, Shruti; Sweet, Elly M et al. (2018) sox2 and sox3 Play unique roles in development of hair cells and neurons in the zebrafish inner ear. Dev Biol 435:73-83
Gou, Yunzi; Guo, Jinbai; Maulding, Kirstin et al. (2018) sox2 and sox3 cooperate to regulate otic/epibranchial placode induction in zebrafish. Dev Biol 435:84-95
Kantarci, Husniye; Gerberding, Andrea; Riley, Bruce B (2016) Spemann organizer gene Goosecoid promotes delamination of neuroblasts from the otic vesicle. Proc Natl Acad Sci U S A 113:E6840-E6848
Kantarci, Husniye; Edlund, Renee K; Groves, Andrew K et al. (2015) Tfap2a promotes specification and maturation of neurons in the inner ear through modulation of Bmp, Fgf and notch signaling. PLoS Genet 11:e1005037
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
Maulding, Kirstin; Padanad, Mahesh S; Dong, Jennifer et al. (2014) Mesodermal Fgf10b cooperates with other fibroblast growth factors during induction of otic and epibranchial placodes in zebrafish. Dev Dyn 243:1275-85
Bhat, Neha; Kwon, Hye-Joo; Riley, Bruce B (2013) A gene network that coordinates preplacodal competence and neural crest specification in zebrafish. Dev Biol 373:107-17
Vemaraju, Shruti; Kantarci, Husniye; Padanad, Mahesh S et al. (2012) A spatial and temporal gradient of Fgf differentially regulates distinct stages of neural development in the zebrafish inner ear. PLoS Genet 8:e1003068
Padanad, Mahesh S; Bhat, Neha; Guo, Biwei et al. (2012) Conditions that influence the response to Fgf during otic placode induction. Dev Biol 364:1-10
Sweet, Elly M; Vemaraju, Shruti; Riley, Bruce B (2011) Sox2 and Fgf interact with Atoh1 to promote sensory competence throughout the zebrafish inner ear. Dev Biol 358:113-21

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