Abstract
The mammalian cochlear duct is tonotopically organized such that the basal cochlea is tuned to high frequency sounds and the apical cochlea to low frequency sounds. In an effort to understand how this tonotopic organization is established, we searched for genes that are differentially expressed along the tonotopic axis during neonatal development. Cochlear tissues dissected from P0 and P8 mice were divided into three equal pieces, representing the base, middle and apex, and gene expression profiles were determined using the microarray technique. The gene expression profiles were grouped according to changes in expression levels along the tonotopic axis as well as changes during neonatal development. The classified groups were further analyzed by functional annotation clustering analysis to determine whether genes associated with specific biological function or processes are particularly enriched in each group. These analyses identified several candidate genes that may be involved in cochlear development and acquisition of tonotopy. We examined the expression domains for a few candidate genes in the developing mouse cochlea. Tnc (tenacin C) and Nov (nephroblastoma overexpressed gene) are expressed in the basilar membrane, with increased expression toward the apex, which may contribute to graded changes in the structure of the basilar membrane along the tonotopic axis. In addition, Fst (Follistatin), an antagonist of TGF-β/BMP signaling, is expressed in the lesser epithelial ridge and at gradually higher levels towards the apex. The graded expression pattern of Fst is established at the time of cochlear specification and maintained throughout embryonic and postnatal development, suggesting its possible role in the organization of tonotopy. Our data will provide a good resource for investigating the developmental mechanisms of the mammalian cochlea including the acquisition of tonotopy.
Highlights
The ability of the mammalian cochlea to respond to sounds of different frequencies is attributable to numerous specializations along the longitudinal axis of the cochlea [1,2]
At P0, the basal half of the cochlea was organized into one row of inner and three rows of outer hair cells with distinct stereociliary hair bundles, while the apical region of the cochlea exhibited multiple rows of unorganized immature hair cells (Fig. 1A), At P4, the entire organ of Corti was in an orderly array with stereocilia of all outer hair cells displaying the characteristic V-shaped (Fig. 1A)
At P8, the morphologies of the hair bundles were almost identical with those of P4, but the angles were generally slightly wider and comparable to those of P21 (Fig. 1C). These results showed that hair cells in the developing cochlea gradually mature in a base-to-apex gradient, and the tonotopic variations along the cochlear duct become evident during neonatal development
Summary
The ability of the mammalian cochlea to respond to sounds of different frequencies is attributable to numerous specializations along the longitudinal (tonotopic) axis of the cochlea [1,2]. Hair cells in the organ of Corti are the mechanosensory receptors that exhibit different sensitivities to specific frequencies depending on their position along the cochlear duct. Their morphological and mechanoelectrical properties gradually differ along the tonotopic axis, which appears to be critical for the frequency tuning [2]. Besides the sensory receptors and neurons, nonsensory structures such as the basilar membrane and tectorial membrane exhibit graded changes in composition and mechanical features. The basilar membrane, which vibrates in response to sound, has been considered as a primary determinant that stimulates the hair cells at a specific position with respect to a specific frequency [5]. Despite numerous structural and cellular specializations in the cochlea that are thought to contribute to tonotopy, the molecular mechanisms that establish these graded specializations during development remain largely unknown
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