2. Development and regeneration of sensory hair cells.
Hearing and balance are mediated by sensory hair cells, named for mechano-sensory cilia projecting from their apical surfaces into the interior of the ear. Sound waves or force from acceleration can deflect cilia, opening mechanically gated ion channels that activate hair cells. In some regions of the inner ear, the tips of hair cell cilia are attached to dense crystals (otoliths) that enhance mechano-transduction. Hair cells are interspersed with support cells, which are required for hair cell survival and also play a vital role in hair cell regeneration (see below).
Sensory Development: We are investigating genes that regulate development of sensory epithelia. Hair cells and support cells are derived from a common pool of precursors (a sensory equivalence group). The transcription factor Atoh1 is known to initiate hair cell differentiation, but we recently found that it also plays an earlier role in establishing the entire equivalence group. Loss of Atoh1 prevents formation of both hair cells and support cells. Additionally, over-expression of Atoh1 using a heat shock-inducible transgene (hsp70-atoh1) leads to dramatic over-production of sensory epithelia containing both support cells and hair cells. The above photos were taken of live embryos in a genetic background in which all hair cells express GFP fluorescence. Excess hair cells can be clearly seen in a hsp70-atoh1 transgenic embryo. Excess support cells are also present but are not visible under these conditions. Note that not all regions of the otic vesicle respond by producing sensory epithelia. We are studying how Atoh1 interacts with other genes to promote sensory competence (the ability to produce sensory epithelia).
Regeneration: Hair cells are sensitive to loud noise or other trauma that can lead to their death. Mammals (including humans) lack the ability to replace lost hair cells, but zebrafish display a robust capacity for hair cell regeneration. To study this process, we kill hair cells using a laser beam and monitor the response over time. As seen here, regeneration occurs within 24 hours after ablation. As hair cells die, nearby support cells undergo “transdifferentiation”. That is, they directly transform into new hair cells.
Identifying genes that regulate regeneration in zebrafish could provide insights for restoring hair cells in humans. We found that the transcription factor Sox2 is required for regeneration. Sox2 is expressed in support cells in both humans and zebrafish, but in mammals the level of expression is much lower. We hypothesize that Sox2 maintains “pluripotency” in support cells, facilitating regeneration.