Transcriptional Control of Sensory Versus Non Sensory Progenitor Specification in the Inner Ear

Abstract

Development of the inner ear requires coordination of early specification, in the correct location, of specific cell types: sensory hair cells, non-sensory supporting cells and sensory neurons that innervate the hair cell. These cells are essential for hearing and balance, acting as mechanosensors for the detection of sound (cochlear region), gravity and acceleration (vestibular region) which are transmitted to the central nervous system. Sensory and nonsensory structures in the functional inner ear are specified early in development, before any overt structure can be seen, according to the spatial location of progenitors within the epithelium of an initial sphere of cells (otocyst). It is thought that the six sensory organs in the inner ear develop from common progenitors in the otic epithelium. We previously discovered that Sox2 is essential for hearing and balance through studying two allelic mouse mutants with recessive deafness and balance-impairment, Light coat and circling (Lcc/Lcc, completely deaf) and Yellow submarine (Ysb/Ysb, severely hearing impaired). We showed that Sox2 is essential for the prosensory and sensory precursors in the inner ear starting from the otocyst stage. In Lcc/Lcc inner ears, all six sensory regions were absent, neither hair cells nor supporting cells differentiate, while the sensory epithelium was severely disrupted in Ysb/Ysb. These phenotypes are due to the severely reduced (Lcc/Lcc) or reduced (Ysb/Ysb) expression of Sox2, specifically within the developing inner ear. We asked whether Sox2 is also essential for specifying the progenitors for the sensory neurons that innervate the hair cells. We found a temporal and dose-dependent requirement for Sox2 in the specification of and/or maintenance of the otic neuroblasts during neurogenesis. Our studies implicate Sox2 as the master specifier for progenitors of the three lineages (sensory neurons, hair cells and supporting cells). We also asked how sensory versus non-sensory fate was controlled in the inner ear. We found Sox2 and BMP/TGFβ signaling function antagonistically to coordinate development of sensory and non-sensory structures in the correct location in the inner ear.