Versican controlled by Lmx1b regulates hyaluronate density and hydration for semicircular canal morphogenesis

Abstract

During inner ear semicircular canal morphogenesis in zebrafish, patterned canal-genesis zones express genes for extracellular matrix component synthesis. These include hyaluronan and the hyaluronan-binding chondroitin sulfate proteoglycan Versican, which are abundant in the matrices of many developing organs. Charged hyaluronate polymers play a key role in canal morphogenesis through osmotic swelling. However, the developmental factor(s) that control the synthesis of the matrix components and regulation of hyaluronate density and swelling are unknown. Here, we identify the transcription factor, Lmx1b, as a positive transcriptional regulator of hyaluronan, Versican, and chondroitin synthesis genes crucial for canal morphogenesis. We show that Versican regulates hyaluronan density through its protein core, whereas the charged chondroitin side chains contribute to the osmotic swelling of hyaluronate. Versican-tuned properties of hyaluronate matrices may be a broadly used mechanism in morphogenesis with important implications for understanding diseases where these matrices are impaired, and for hydrogel engineering for tissue regeneration. Summary StatementHere, we reveal the function of the hyaluronan-binding proteoglycan, Versican, and its chondroitin sulfate side chains in tuning the density and hydration of the hyaluronate-rich ECM to generate force, under the control of the transcription factor Lmx1b for successful inner ear semicircular canal morphogenesis in zebrafish.