The generation of the mechanosensory elements of the inner ear during development proceeds in a precise temporal and spatial pattern. First, neurosensory precursors form sensory neurons. Then, prosensory patches emerge and give rise to hair and supporting cells. Hair cells are innervated by cochleovestibular neurons that convey sound and balance information to the brain. SOX2 is an HMG transcription factor characteristic of the stem-cell genetic network responsible for progenitor self-renewal and commitment, and its loss of function generates defects in ear sensory epithelia. The present study shows that SOX2 protein is expressed in a spatially and temporally restricted manner throughout development of the chick inner ear. SOX2 is first expressed in the neurogenic region that gives rise to sensory neurons. SOX2 is then restricted to the prosensory patches in E4 and E5 embryos, as revealed by double and parallel labelling with SOX2 and Tuj1, MyoVIIa, or Islet1. Proliferating cell nuclear antigen labelling showed that SOX2 is expressed in proliferating cells during those stages. By E5, SOX2 is also expressed in the Schwann cells of the cochleovestibular ganglion, but not in the otic neurons. At E8 and E17, beyond stages of sensory cell specification, SOX2 is transiently expressed in hair cells, but its level remains high in supporting cells. SOX3 is concomitantly expressed with SOX2 in the neurogenic domain of the otic cup, but not in prosensory patches. Our data are consistent with a role for SOX2 in specifying a population of otic progenitors committed to a neural fate, giving rise to neurons and hair cells.
Bone morphogenetic proteins (BMPs) are diffusible molecules involved in a variety of cellular interactions during development. Bmp4 expression accompanies the development of the ear sensory organs during patterning and specification of sensory cell fates, yet there is no understanding of the role of BMP4 in this process. The present work was aimed at exploring the effects of BMP-signaling on the development of hair-cells. For this purpose, we studied gene expression, cell proliferation and cell death in isolated chick otic vesicles that were grown in vitro in the presence of recombinant BMP4 or the BMP-inhibitor Noggin. Cath1 was used as a marker for hair-cell specification. BMP4 reduced the number of Cath1-cells and, conversely, Noggin increased the size of the sensory patches and the number of Cath1-positive cells. The effect of BMP4 was irreversible and occurred before hair-cell specification. Lfng and Fgf10 were expressed in the prosensory domain before Cath1, and their expression was expanded by Noggin. At these stages, modifications of BMP activity did not respecify non-sensory epithelium of the otic vesicle. The expression of Bmp4 at sensory patches was suppressed by BMP4 and induced by Noggin suggesting an autoregulatory loop. Analysis of BrdU incorporation during 6 and 18 h indicated that the effects of BMP4 were due to its ability to reduce the number of actively proliferating progenitors and inhibit cell fate specification. BMP4 induced cell death within the prosensory domain of the otic vesicle, along with the expression of Msx1, but not Msx2. On the contrary, BMP-inhibition with Noggin favored hair-cell specification without changes in the overall cell proliferation. We propose that about the stage of terminal division, the balance between BMP and BMP-inhibitory signals regulates survival and specification of hair-cell precursors, the final number of sensory hair-cells being limited by excess levels of BMPs. The final size of sensory patches would hence depend on the balance between BMP4 and opposing signals.
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