Thyroid Hormone-deficient Period Prior to the Onset of Hearing Is Associated with Reduced Levels of β-Tectorin Protein in the Tectorial Membrane

Abstract

The genes for ␣-and ␤-tectorin encode the major noncollagenous proteins of the tectorial membrane. Recently, a targeted deletion of the mouse ␣-tectorin gene was found to cause loss of cochlear sensitivity (1). Here we describe that mRNA levels for ␤-tectorin, but not ␣-tectorin, are significantly reduced in the cochlear epithelium under constant hypothyroid conditions and that levels of ␤-tectorin protein in the tectorial membrane are lower. A delay in the onset of thyroid hormone supply prior to onset of hearing, recently described to result in permanent hearing defects and loss of active cochlear mechanics (2), can also lead to permanently reduced ␤-tectorin protein levels in the tectorial membrane. ␤-Tectorin protein levels remain low in the tectorial membrane up to one year after the onset of thyroid hormone supply has been delayed until postnatal day 8 or later and are associated with an abnormally structured tectorial membrane and the loss of active cochlear function. These data indicate that a simple delay in thyroid hormone supply during a critical period of development can lead to low ␤-tectorin levels in the tectorial membrane and suggest for the first time that ␤-tectorin may be required for development of normal hearing.It has been known for many years that thyroid hormone (TH) 1 is necessary for normal development of the auditory system (3-5). Both genetic and acquired neonatal TH deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and the success of delayed, corrective TH treatment has recently been investigated (2, 6). These studies revealed that maternal TH prior to the onset of thyroid gland function, as well as TH supply beyond the onset of hearing at postnatal day 12 (P12), was not critical for the development of normal hearing in rats (2, 6). However, within the crucial period of time any delay in the rise of TH plasma levels (transient hypothyroidism) leads to permanent hearing defects, though the organ of Corti develops to an organ without obvious structural or neuronal abnormalities (2). Analysis of distortion product otoacoustic emissions revealed that the active cochlear process was TH-dependent and was permanently lost following the induction of a transient TH-free period between E17 and ϾP8 (2). Distortion product otoacoustic emissions are sounds that emanate from the ear and are believed to be produced by the interaction of actively amplified traveling waves on the basilar membrane (7-9). The tectorial membrane plays a crucial role in this active process, because it couples transverse, sound-induced, basilar membrane motion to a radial deflection of the sensory hair bundles. In former studies with rodents (10, 11) it has been observed that the tectorial membrane is distorted as a result of constant hypothyroidism. The major non-collagenous components of the tectorial membrane, ␣-and ␤-tectorin, were identified recently as the products of single copy genes (12). Missen...

The Influence of Thyroid Hormone Deficiency on the Development of Cochlear Nonlinearities

“…For example, in α-tectorindeficient mice, although affected animals are insensitive to tonal stimulation, frequency tuning remains sharp even though the TM is detached from the spiral limbus according to Legan et al (2000). In the case of β-tectorin-deficient mice, although the second, lowfrequency resonance reported by Legan et al (2000) was not observed, Russell et al (2007) reported that high-frequency tuning sharpness is actually enhanced at CF relative to normal animals even though the TM is enlarged and exhibits the disrupted striated-sheet matrix described previously in hypothyroid rats that also exhibit reduced levels of β-tectorin (Knipper et al 2001). While it is important to replicate these findings and to determine if they generalize to other models, these data generally suggest that the link between TM structure and composition and the sharpness of tuning may be more complex than previously thought.…”

“…While many inner and middle ear anomalies have been reported in hypothyroid animals, the most commonly and consistently reported defects are limited to those associated with the tectorial membrane (TM) and cochlear innervation (Deol 1973, 1976; Anniko and Rosenkvist 1982;Uziel et al 1981Uziel et al , 1983aUziel et al , b, 1985Remezal and Gil-Loyzaga 1993;Rusch et al 2001;Knipper et al 2001;Griffith et al 2002;Christ et al 2004;Johnson et al 2007). Of these, the TM has received the greatest amount of attention as a prospective source of pathology, in part, no doubt, because of its imposing presence and distorted character, as shown in histological section under some circumstances.…”

Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

“…Data from models of severe and prolonged hypothyroidism have established a catalog of events in the developing cochlea, brain, and bone that depend on thyroid hormone. This catalog includes opening of the tunnel in the organ of Corti of the cochlea at P5-P8 (18,49), shaping of the tectorial membrane in the cochlea through the expression of the tectorial membrane-specific proteins ␣-tectorin (coded by the gene Tecta) and ␤-tectorin (coded by the gene Tectb) (31,45), arrival of efferent innervation at cochlear outer hair cells (12,60), expression of the neuron-specific gene synaptotagmin Srg1 (20,44), and the maturation and mineralization of bone-forming chondrocytes and mesenchymal cells (1,52). The cochlea controls T3 levels locally through the expression of two deiodinases, Dio2 and Dio3, and is therefore somewhat independent of circulating levels of T3 if sufficient amounts of T4 are provided (11,39).…”

Deletion of the Ca2+-activated potassium (BK) α-subunit but not the BKβ1-subunit leads to progressive hearing loss

“…Western Blot analysis from cochlea tissue was performed as described (24). The specifity of the KCNQ4 antibody was verified by preadsorbing the antibody with the antigenic peptide.…”