Abstract
The mammalian auditory sensory epithelium has one of the most stereotyped cellular patterns known in vertebrates. Mechano-sensory hair cells are arranged in precise rows, with one row of inner and three rows of outer hair cells spanning the length of the spiral-shaped sensory epithelium. Aiding such precise cellular patterning, differentiation of the auditory sensory epithelium is precisely timed and follows a steep longitudinal gradient. The molecular signals that promote auditory sensory differentiation and instruct its graded pattern are largely unknown. Here, we identify Activin A and its antagonist follistatin as key regulators of hair cell differentiation and show, using mouse genetic approaches, that a local gradient of Activin A signaling within the auditory sensory epithelium times the longitudinal gradient of hair cell differentiation. Furthermore, we provide evidence that Activin-type signaling regulates a radial gradient of terminal mitosis within the auditory sensory epithelium, which constitutes a novel mechanism for limiting the number of inner hair cells being produced.
Highlights
Housed in the inner ear cochlea, the auditory sensory organ contains a spiral shaped sensory epithelium specialized to detect and transduce sound
We find that in the developing murine cochlea Activin A acts as a pro-differentiation signal, and demonstrate that a counter gradient of Activin A and FST within the auditory sensory epithelium times the basal-to-apical wave of hair cell differentiation
The graded pattern of Activin A expression parallels auditory hair cell differentiation The biological activity of Activins and other Activin-type ligands is limited by the secreted protein follistatin (FST)
Summary
Housed in the inner ear cochlea, the auditory sensory organ contains a spiral shaped sensory epithelium specialized to detect and transduce sound. To ensure the highly stereotyped arrangement of hair cells, cell cycle withdrawal and differentiation within the auditory sensory epithelium occurs in a spatially and temporally highly coordinated manner. Auditory sensory progenitors (pro-sensory cells) exit the cell cycle in an apical-to-basal gradient (Chen et al, 2002; Lee et al, 2006; Ruben, 1967), whereas their differentiation into hair cells and supporting cells occurs in an opposing, basal-to-apical gradient (Chen et al, 2002). Pro-sensory cells are exposed to high concentrations of SHH protein secreted by the adjacent spiral ganglion neurons (SGNs) (Bok et al, 2013; Liu et al, 2010). SHH signaling represses hair cell differentiation, at least in part, through maintaining the expression of HEY1 and HEY2 in pro-sensory cells
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