The mammalian inner ear contains six sensory organs that function to maintain balance and transduce sound information. Housed in each region are three fundamental cell types necessary for generating a neurosensory response: mechanosensory hair cells, supporting cells, and innervating neurons. Interestingly all three cell types arise from the otic placode. Lineage studies have demonstrated that hair cells and supporting cells arise from a common sensory progenitor, and in some regions all three cell types can originate from a common neurosensory progenitor. However, it is not well understood what molecular mechanisms specify these distinct cell fates. One molecule shown to play role in these processes is the HMG transcription factor SOX2. Loss of function mutations in the Sox2 locus results in inner ears with gross morphological impairments and a loss of sensory progenitors. Overexpression studies have demonstrated SOX2's sufficiency in promoting inner ear neurogenesis. These experiments have lead investigators to conclude that SOX2 is a neurosensory marker that acts cell autonomously. However, the spatial and temporal requirements for SOX2 in normal inner ear development are currently unknown. Discovering whether SOX2 actually marks the sensory and neural progenitors throughout early otic development, and at what point expression is required for different sensory and neural regions to develop, is an important goal for understanding the how inner ear neurosensory and non- sensory regions are established. Through the use of genetic recombination-based strategies, the location of early SOX2 expression will be mapped and its biological significance in these areas tested with timed-deletion experiments. Preliminary results suggest that SOX2 may be critical for generating both sensory and non- sensory cell fates, as well as for inner ear neurogenesis. Increasing our knowledge regarding mechanisms in which inner ear progenitors are specified and undergo differentiation is an important goal for future cell replacement therapies aimed at addressing hearing and balance disorders.
Hearing and vestibular disorders commonly occur from loss or damage to critical cell types (hair cells, supporting cells, and cochleovestibular (CVG) neurons), which in mature mammals, are not replaced. Potential therapeutic strategies to treat these disorders may involve cell replacement or regenerative therapies; however, a prerequisite for this approach is an understanding of how sensory and neural progenitors normally are specified to adopt distinct cell fates. Elucidating the spatiotemporal requirements of the transcription factor SOX2, previously implicated in both neural and sensory specification in the ear, will create insights into the molecular mechanisms through which sensory progenitors are generated; this knowledge will provide a platform for future therapies designed to restore inner ear function.
| Steevens, Aleta R; Sookiasian, Danielle L; Glatzer, Jenna C et al. (2017) SOX2 is required for inner ear neurogenesis. Sci Rep 7:4086 |
