Auditory supporting cells (SCs) are essential for the proper development, survival and function of mechano- sensory hair cells (HCs) and their innervating neurons. Defects in the biophysical properties or function of SCs result in auditory dysfunction and hearing loss. Despite their importance the molecular mechanisms that control their development and function are largely unknown. A main objective of our proposed study is to uncover the molecular mechanisms that guide auditory SCs development and function. We recently uncovered that Notch signaling instructs SC development in the murine cochlea. Here in this proposed study we will determine the Notch ligand(s) and receptor(s) that control SC differentiation and survival (aim1) as well characterize potential novel roles for Notch signaling and its targets in SC-guided cochlear innervation and auditory function (aim2). Our proposed studies will advance our understanding of how Notch signaling operates in differentiating SCs as wells as provide new insights into how SCs guide neuronal innervation as well as control cochlear homeostasis. A second major objective of our proposed study is to uncover the molecular mechanisms that control the developmental decline of SCs plasticity in the mammalian cochlea. HC loss in mammals is permanent and is a leading cause for deafness in humans. In non- mammalian vertebrates SCs regenerate lost HCs throughout the lifetime of the animal. In mammals, young immature SCs can be coaxed into regenerating lost HCs by inhibiting Notch signaling or over-stimulation of wnt signaling; however, the ability of murine auditory SC to respond to such regenerative stimuli rapidly declines after the first postnatal week. We recently uncovered that the RNA binding protein LIN28B enhances HC production in the immature cochlea in response to Notch signaling.
In aim3 we will investigate how LIN28B/let- 7 axis modifies the regenerative response of the immature SCs, as well as address whether LIN28B re- expression in mature SCs enhances their ability to respond to Notch inhibition and regenerate lost HCs. Findings from the proposed experiments could identify new therapeutic targets and lead to novel therapeutic approaches in the treatment of HC loss and eventual cure of deafness.
It is believed that lack of hair cell regeneration in mammals is due to an inability of neighboring supporting cells to regenerate damaged hair cells. In our proposal, we will characterize the molecular mechanisms instructing supporting cell differentiation and maintenance to elucidate why supporting cells fail to de-differentiate and regenerate lost hair cells. We believe that our findings will shed light on the molecular machinery that restrict hair cell regeneration and could provide new targets for future hair cell replacement therapies.
| Doetzlhofer, Angelika; Avraham, Karen B (2017) Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration. Semin Cell Dev Biol 65:69-79 |
| Basch, Martin L; Brown 2nd, Rogers M; Jen, Hsin-I et al. (2016) Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates. Elife 5: |
| Campbell, Dean P; Chrysostomou, Elena; Doetzlhofer, Angelika (2016) Canonical Notch signaling plays an instructive role in auditory supporting cell development. Sci Rep 6:19484 |
| Golden, Erin J; Benito-Gonzalez, Ana; Doetzlhofer, Angelika (2015) The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea. Proc Natl Acad Sci U S A 112:E3864-73 |
| Korrapati, Soumya; Roux, Isabelle; Glowatzki, Elisabeth et al. (2013) Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea. PLoS One 8:e73276 |
