A large proportion of deafness and vestibular disorders are caused by loss or dysfunction of critical cell types in the inner ear, including hair cells, supporting cells and cochleovestibular neurons. Thus, in order to treat many forms of inner ear dysfunction, a thorough understanding of how these cell types form is a necessary prerequisite for designing cell regeneration or replacement therapies. Lineage studies have demonstrated that these cell types can arise from a common progenitor. Thus, one approach to regenerating or replacing these cell types is through the generation of these multipotent progenitors. The long-term goal of this research program is to understand the molecular mechanisms that control specification of the neurosensory progenitors, as well as the factors controlling the generation of the different cell types arising from these progenitors. Although we are beginning to understand some of the factors that are important in the lineage of the sensory progenitors, there are still many fundamental questions that remain unanswered, including how and when the sensory progenitors are generated. The SRY-box transcription factor SOX2 is an essential factor for sensory progenitor development. Loss of function studies in the mouse have shown that SOX2 is a critical factor for development of the sensory progenitors, as deletion of SOX2 leads to complete absence of all hair cells and supporting cells in the inner ear epithelium. However, we still have little understanding of how and when SOX2 acts in the development of these important progenitors. In this proposal we will focus on understanding how SOX2 acts to generate the sensory regions. Specifically, to define the spatial and temporal requirements for SOX2 function, we will use a newly-generated inducible mouse Cre allele to fate map SOX2-expressing cells and perform timed-deletion experiments (Aim I and II).
In Aim III we will investigate whether SOX2 is capable of producing ectopic sensory regions in the postnatal and adult inner ear. Finally, we will test whether JAG1- mediated Notch signaling, which is also critical in the generation of the sensory progenitors, acts upstream of SOX2 by performing rescue experiments (Aim IV). Together, these experiments will reveal fundamental aspects of SOX2 function and further elucidate the potential of SOX2 in regenerating or replacing critical cell types in the ear through generation of the sensory progenitors.
Three cell types are commonly affected in deafness and vestibular disorders, including hair cells, supporting cells and cochleovestibular neurons, all of which can arise from a common progenitor. This proposal will elucidate the molecular cascade leading to the generation of these important multipotent progenitors. Understanding the generation of these critical neurosensory progenitors will provide novel approaches for treating deafness and vestibular dysfunction through regenerative or cell replacement therapies.
