Hair cells within the inner ear transform sound stimuli into electrical impulses to then be transmitted to the brain by afferent neurons. Hearing is lost in individuals where hair cells are absent or dysfunctional hearing is lost. One of the major hurdles in hair cell restoration is that after hair cell death, the sensory organ of Corti is eventually replaced by a flat cuboidal epithelium. Pst research has shown that these cells are not receptive to transdifferentation into hair cells. Therefore, it is critical to define the molecules that give rise to the prosensory epithelia and provide the underlying gene regulatory network that support transcription factors involved in hair cell differentiation. Towards this end, we have identified early otic Gata3 expression is necessary for prosensory specification and hair cell differentiation. In addition, the level of Gata3 is severely reduced in the flat epithelium that replaces the organ of Corti after hair cell loss. Gata3 continues to be expressed in the developing prosensory epithelia and hair cells as they differentiate, however, its later expression during these events has not been characterized. Based upon these observations, we hypothesize that the continued expression of precise levels of Gata3 are continually needed during the development and differentiation of prosensory epithelia and hair cells. We will test this hypothesis by investigating 1) the loss of Gata3 during these time points and its effect on the specification of cells to adopt a prosensory fate and on hair cells to correctly differentiate, 2) increased expression of Gata3 during these time points and how this increased level effects these cell types, and 3) if Gata3 expression can alter the flat epithelium into a more sensory like state. Finally, this research will lay the foundation and provide preliminary data for a subsequent R01.
The sense of hearing hinges upon transduction of sound energy into electrical impulses by hair cells located in the inner ear. Although Atoh1 is necessary for the differentiation and survival of hair cells its function depends upon prior and continued expression of other transcription factors. This proposal seeks to better understand one of these factors, Gata3, and its unknown role in sensory specification and hair cell differentiation.