Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti

Abstract

The transcription factor Sox2 is both necessary and sufficient for the generation of sensory regions of the inner ear. It regulates expression of the Notch ligand Jag1 in prosensory progenitors, which signal to neighboring cells to up-regulate Sox2 and sustain prosensory identity. However, the expression pattern of Sox2 in the early inner ear is very broad, suggesting that Sox2-expressing progenitors form a wide variety of cell types in addition to generating the sensory regions of the ear. We used Sox2-CreER mice to follow the fates of Sox2-expressing cells at different stages in ear development. We find that Sox2-expressing cells in the early otocyst give rise to large numbers of non-sensory structures throughout the inner ear, and that Sox2 only becomes a truly prosensory marker at embryonic day (E)11.5. Our fate map reveals the organ of Corti derives from a central domain on the medial side of the otocyst and shows that a significant amount of the organ of Corti derives from a Sox2-negative population in this region.

Dynamic Expression of Sox2, Gata3, and Prox1 during Primary Auditory Neuron Development in the Mammalian Cochlea

“…At this stage we observed that while neurons did not express Sox2 protein, Sox2-EGFP was present at E12.75 (Fig 1C, blue arrows) likely due to the longer half-life of EGFP [36]. Moreover, we also observed cells in the otocyst that are positive for Sox2-EGFP but negative for Sox2 protein (Fig 1C, pink arrows), agreeing with a previous report showing that Sox2-expressing cells in the early otocyst give rise to large numbers of Sox2 negative cochlear non-sensory epithelial cells [10]. Altogether our data indicate that migrating glial cells expressed Sox2 but post-mitotic neurons in the CVG downregulated Sox2 (blue arrows in Fig 1C represent Sox2-EGFP + /Sox2 - neurons, and yellow arrows represent Sox2-EGFP + /Sox2 + glial cells.…”

“…We examined spatiotemporal expression of Sox2 and Sox10 in the developing cochlea focusing on cells in the spiral ganglion. Our results demonstrated Sox2 expression levels had two peaks at the delamination of neuroblasts from otocyst and around birth, in general agreement with the previously reported expression patterns of Sox2 in developing avian [56] and mouse [8] inner ear, and with lineage tracing studies of Sox2 [10]. In summary, Sox2 was first expressed in delaminating neuroblasts and its downregulation is necessary for progression of neurogenesis by Neurogenin1 and NeuroD1 [57].…”

“…Neuronal precursors delaminate from the otocyst at the early stage of inner ear development and form PANs [2]. A number of transcription factors that are involved in neurogenesis as well as specification of PANs have been identified: Neurog1 [3, 4], NeuroD1 [5], Gata3 [6, 7] and Sox2 [8–10]. There are two types of PANs.…”

Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance

“…The very early expression of Sox2 through the otic placode overlaps with the earliest forming neurons710 and it is expressed in both neurogenic and sensory progenitors11. Sox2 may also be involved in non-sensory development12. Experimental data indicate that there are complex antagonistic and cooperative interactions between Sox2 and bHLH transcription factors during the development of the inner ear.…”

“…We chose Isl1-cre to achieve a partial overlap of cre and Sox2 expression in the sensory epithelium and delaminating neurons in the inner ear11121617. The delayed elimination of Sox2 by Isl1-cre does not affect the earliest specification events in the developing ear, as these Isl1-cre;Sox2 f/f mutants show an initial formation of vestibular neurons and spiral ganglion (SG) neurons in the cochlear base.…”