The goal of our research is to understand the timing and molecular mechanisms that control patterning and cell fate specification in the developing inner ear. The inner ear, unique to vertebrates, houses the peripheral receptors for the sensations of hearing and balance. It is composed of a complex three-dimensional arrangement of constituent cells which includes neurons, receptors grouped into distinct sensory organs, and non-sensory tissues that form the ducts, tubules and specialized secretory epithelia needed for proper homeostasis of the fluid components. In humans and animal models, disruption of the precise morphology of the inner ear due to congenital defects or disease can result in deafness and/or to difficulties with balance and equilibrium. Our efforts to understand the fundamental defects that result in inner ear abnormalities are focused on both the normal processes of development and on the cascade of events that can arise as a result of specific genetic defects. In this study, we focus on Wnt signaling. This family of signaling molecules has been highly conserved during evolution, and is linked to many aspects of development including control of cell proliferation, cell fate specification, morphogenetic movements, axon guidance and orientation of cells along the body axis. We have completed a comprehensive mapping of the spatial and temporal expression patterns of 28 Wnt-related genes during development of the avian inner ear. Our survey included ligands, receptors and secreted inhibitors. The data have led to several hypotheses about the role of Wnts in different aspects of ear development.
The Specific Aims are (1) to explore the function of Wnt/2-catenin signaling as a switch between auditory and vestibular (macular) sensory organ fates in the cochlear duct;(2) to explore the function of Wnt signaling as a repulsive axon guidance cue in the developing inner ear;and (3) to explore the function of radial gradients of Wnt-related molecules across the auditory sensory epithelium. Our findings may provide baseline data for therapeutic strategies to direct stem cells along different developmental fates for repair or replacement of damaged inner ear cells. Our research program uses the chicken embryo to study the molecular pathways underlying development of the inner ear. The long-term goal of our research is to determine whether the molecules we identify may be linked to genetic causes of congenital deafness in humans, with the hope that this knowledge might be applied to therapeutic treatments aimed at the regeneration or repair of inner ear cells.
Our research program uses the chicken embryo to study the molecular pathways underlying development of the inner ear. The long-term goal of our research is to determine whether the molecules we identify may be linked to genetic causes of congenital deafness in humans, with the hope that this knowledge might be applied to therapeutic treatments aimed at the regeneration or repair of inner ear cells.
|Munnamalai, Vidhya; Fekete, Donna M (2017) Building the human inner ear in an organoid. Nat Biotechnol 35:518-520|
|Munnamalai, Vidhya; Sienknecht, Ulrike J; Duncan, R Keith et al. (2017) Wnt9a Can Influence Cell Fates and Neural Connectivity across the Radial Axis of the Developing Cochlea. J Neurosci 37:8975-8988|
|Nishitani, Allison M; Ohta, Sho; Yung, Andrea R et al. (2017) Distinct functions for netrin 1 in chicken and murine semicircular canal morphogenesis. Development 144:3349-3360|
|Lutz, Gabriel; Jurak, Igor; Kim, Eui Tae et al. (2017) Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors. Viruses 9:|
|Stoller, Michelle L; Fekete, Donna M (2016) Tol2-Mediated Delivery of miRNAs to the Chicken Otocyst Using Plasmid Electroporation. Methods Mol Biol 1427:27-42|
|Munnamalai, Vidhya; Fekete, Donna M (2016) Notch-Wnt-Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner. Development 143:4003-4015|
|Munnamalai, Vidhya; Fekete, Donna M (2016) Organotypic Culture of the Mouse Cochlea from Embryonic Day 12 to the Neonate. Methods Mol Biol 1427:293-303|
|Zhang, Kaidi D; Stoller, Michelle L; Fekete, Donna M (2015) Expression and Misexpression of the miR-183 Family in the Developing Hearing Organ of the Chicken. PLoS One 10:e0132796|
|Battisti, Andrea C; Fantetti, Kristen N; Moyers, Bryan A et al. (2014) A subset of chicken statoacoustic ganglion neurites are repelled by Slit1 and Slit2. Hear Res 310:1-12|
|Jiang, Han; Wang, Lingyan; Beier, Kevin T et al. (2013) Lineage analysis of the late otocyst stage mouse inner ear by transuterine microinjection of a retroviral vector encoding alkaline phosphatase and an oligonucleotide library. PLoS One 8:e69314|
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