Abstract
Tsukushi (TSK)—a small, secreted, leucine-rich-repeat proteoglycan—interacts with and regulates essential cellular signaling cascades. However, its functions in the mouse inner ear are unknown. In this study, measurement of auditory brainstem responses, fluorescence microscopy, and scanning electron microscopy revealed that TSK deficiency in mice resulted in the formation of abnormal stereocilia in the inner hair cells and hearing loss but not in the loss of these cells. TSK accumulated in nonprosensory regions during early embryonic stages and in both nonprosensory and prosensory regions in late embryonic stages. In adult mice, TSK was localized in the organ of Corti, spiral ganglion cells, and the stria vascularis. Moreover, loss of TSK caused dynamic changes in the expression of key genes that drive the differentiation of the inner hair cells in prosensory regions. Finally, our results revealed that TSK interacted with Sox2 and BMP4 to control stereocilia formation in the inner hair cells. Hence, TSK appears to be an essential component of the molecular pathways that regulate inner ear development.
Highlights
Tsukushi (TSK) is a small, secreted leucine-rich-repeat proteoglycan and extracellular signaling molecule that participates in various developmental processes in vertebrates [1,2,3]
At E13.5 and E15.5, TSK-expressing cells were detected at the lateral wall of the cochlear duct, which would later differentiate into the stria vascularis and spiral ligament, and not to spiral ganglion cells (SGCs) (Fig. 1c-h)
At postnatal stage 0 (P0), TSK-expressing cells were observed in some SGCs, the OC, inside and outside of the lateral wall that differentiates into the stria vascularis and spiral ligaments, and the greater epithelial ridge, which differentiates into the spiral limbus and tectorial membrane (Fig. 1i-k)
Summary
Tsukushi (TSK) is a small, secreted leucine-rich-repeat proteoglycan and extracellular signaling molecule that participates in various developmental processes in vertebrates [1,2,3]. The diverse functions of TSK depend on its ability to bind and interact with various intermediate molecules of some major signaling pathways. TSK interactions with BMP, FGF, TGF-β, and Wnt signaling pathways have been previously reported [1, 4,5,6] and shown to affect the development of the central nervous networks [7, 8], as well as wound healing [9]. We studied TSK expression and function during inner ear morphogenesis and after birth. We investigated the molecular mechanisms of TSK interaction with BMP4 by immunostaining and assessing mRNA expression levels. We investigated specific effects of TSK deficiency on stereocilia of the hair cells (HCs), while leaving the rest of the inner ear morphologically intact
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