Conserved role of Sonic Hedgehog in tonotopic organization of the avian basilar papilla and mammalian cochlea

Abstract

Sound frequency discrimination begins at the organ of Corti in mammals and the basilar papilla in birds. Both of these hearing organs are tonotopically organized such that sensory hair cells at the basal (proximal) end respond to high frequency sound, whereas their counterparts at the apex (distal) respond to low frequencies. Sonic hedgehog (Shh) secreted by the developing notochord and floor plate is required for cochlear formation in both species. In mice, the apical region of the developing cochlea, closer to the ventral midline source of Shh, requires higher levels of Shh signaling than the basal cochlea farther away from the midline. Here, gain-of-function experiments using Shh-soaked beads in ovo or a mouse model expressing constitutively activated Smoothened (transducer of Shh signaling) show up-regulation of apical genes in the basal cochlea, even though these regionally expressed genes are not necessarily conserved between the two species. In chicken, these altered gene expression patterns precede morphological and physiological changes in sensory hair cells that are typically associated with tonotopy such as the total number of stereocilia per hair cell and gene expression of an inward rectifier potassium channel, IRK1, which is a bona fide feature of apical hair cells in the basilar papilla. Furthermore, our results suggest that this conserved role of Shh in establishing cochlear tonotopy is initiated early in development by Shh emanating from the notochord and floor plate.frequency discrimination | regional identity | Inhba | A2m | Efnb2

The acquisition of positional information across the radial axis of the cochlea

“…This, in turn, leads to the premature differentiation of hair cells. Most recently, the longitudinal expression of the Inhba (Activin A subunit inhibin bA) and Fst (Follistatin) genes were found to be influenced by Shh regulation . It was found that a counter‐gradient activity of Activin A and Fst regulates both hair cell differentiation and cell cycle exit along the longitudinal axis .…”

“…Most recently, the longitudinal expression of the Inhba (Activin A subunit inhibin bA) and Fst (Follistatin) genes were found to be influenced by Shh regulation. 106 It was found that a countergradient activity of Activin A and Fst regulates both hair cell differentiation and cell cycle exit along the longitudinal axis. 107 Even though the Shh pathway was primarily associated with timing of differentiation along the longitudinal axis, we included it because it is an important morphogen and it is critical for regulating the timing of cochlear development.…”

Activin signaling informs the graded pattern of terminal mitosis and hair cell differentiation in the mammalian cochlea

“…Auditory sensory progenitors (pro-sensory cells) exit the cell cycle in an apical-to-basal gradient 48 (Ruben, 1967;Chen and Segil, 1999;Lee et al, 2006), whereas their differentiation into hair 49 cells and supporting cells occurs in an opposing, basal-to-apical gradient (Chen et al, 2002). 50 4 gradient within the differentiating auditory sensory epithelium (Son et al, 2015). Activins, which 78 belong to the transforming growth factor (TGF)-β superfamily of cytokines, control a broad range 79 of biological processes, including reproduction, embryonic axial specification, organogenesis 80 and adult tissue homeostasis (reviewed in (Namwanje and Brown, 2016)).…”

Fate‐mapping analysis using Rorb‐IRES‐Cre reveals apical‐to‐basal gradient of Rorb expression in mouse cochlea

“…3 The inner ear SE typically contains mechanosensitive receptors, the hair cells (HCs) and neighboring supporting cells (SCs); however, the HCs and SCs in each individual present unique morphological and geneexpression profiles. [8][9][10] Moreover, the distinct developmental properties of the HCs and SCs at each cochlear turn contribute to the tonotopic axis. The mammalian cochlea harbors two types of HCs, outer HCs (OHCs) and inner HCs (IHCs), which are, respectively, sound amplifiers and primary sensory cells.…”

“…Recent studies suggest that Shh, retinoic acid, and Bmp7 contribute to tonotopic axis formation, and their dysregulation leads to defective frequency distribution. [8][9][10] Moreover, the distinct developmental properties of the HCs and SCs at each cochlear turn contribute to the tonotopic axis.…”