Auditory neuropathy caused by the loss of spiral ganglion neurons (SGN) loss results in hearing loss. Standard remediation, such as the use of hearing aids and cochlear implants are ineffective after the loss of SGNs. Many daily ototoxic insults such as loud sounds result in acute loss of synaptic contacts, degeneration of the auditory nerve fibers and loss of SGN over an extended period of time. Given an ever-increasing aging population that is exposed to loud sounds from portable music players, degeneration of SGNs will become a major health concern. Stem cell replacement therapies hold great promise to repopulate lost SGNs and restore hearing function. In order to properly use stem cells to treat hearing loss, identifying genes that can recapitulate SGN development in stem cells will accelerate efforts for replacement therapies. Using an immortalized otic progenitor (iMOP) cell line, we identified novel candidate transcription factors and chromatin remodeling proteins that are important in SGN development and regeneration. One of the candidates is Chd4, a chromatin remodeling protein that is part of the nucleosome remodeling and deacetylase (NuRD) complex. We propose that Chd4 is essential for neuronal specification, axon guidance and synaptogenesis during SGN development. We will test the role of Chd4 in specifying neuronal fate and neurite extension using iMOP-derived neurons and an inner ear Chd4 knockout animal. Using an iMOP-derived neuron and deafferented cochlear explant co-culture system, we will study how Chd4 promotes axon guidance to the hair cell targets. Finally, we will generate a tamoxifen inducible Chd4 knockout animal to determine defects in synaptogenesis during SGN maturation.
Auditory neuropathy caused by the loss of spiral ganglion neurons (SGN) currently has no treatment options. Stem cell replacement therapy has emerged as a promising avenue to address this significant health concern. Identifying and understanding the function of genes involved in SGN development will accelerate efforts for stem cell therapies.
|Chen, Justin Y; Parekh, Miloni; Seliman, Hadear et al. (2018) Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction. J Biol Chem 293:15581-15593|
|Zappia, Katherine J; O'Hara, Crystal L; Moehring, Francie et al. (2017) Sensory Neuron-Specific Deletion of TRPA1 Results in Mechanical Cutaneous Sensory Deficits. eNeuro 4:|
|Norris, Anne; Tammineni, Prasad; Wang, Simon et al. (2017) SNX-1 and RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes. Proc Natl Acad Sci U S A 114:E307-E316|
|Song, Zhichao; Jadali, Azadeh; Fritzsch, Bernd et al. (2017) NEUROG1 Regulates CDK2 to Promote Proliferation in Otic Progenitors. Stem Cell Reports 9:1516-1529|
|Li, Ying; Tzatzalos, Evangeline; Kwan, Kelvin Y et al. (2016) Transcriptional Regulation of Notch1 Expression by Nkx6.1 in Neural Stem/Progenitor Cells during Ventral Spinal Cord Development. Sci Rep 6:38665|
|Vogl, Christian; Panou, Iliana; Yamanbaeva, Gulnara et al. (2016) Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing. EMBO J 35:2536-2552|
|Azadeh, Jadali; Song, Zhichao; Laureano, Alejandra S et al. (2016) Initiating Differentiation in Immortalized Multipotent Otic Progenitor Cells. J Vis Exp :|
|Kwan, Kelvin Y (2016) Single-Cell Transcriptome Analysis of Developing and Regenerating Spiral Ganglion Neurons. Curr Pharmacol Rep 2:211-220|
|Jadali, Azadeh; Kwan, Kelvin Y (2016) Activation of PI3K signaling prevents aminoglycoside-induced hair cell death in the murine cochlea. Biol Open 5:698-708|
|Patel, Sahishnu; Chueng, Sy-Tsong Dean; Yin, Perry T et al. (2015) Induction of stem-cell-derived functional neurons by NanoScript-based gene repression. Angew Chem Int Ed Engl 54:11983-8|