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 pattern 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 hydration of hyaluronate-containing extracellular matrices. Versican-tuned properties of hyaluronate matrices may be a broadly used mechanism in morphogenesis with important implications for understanding diseases in which these matrices are impaired, and for hydrogel engineering for tissue regeneration.
Footnotes
Author contributions
Conceptualization: A.M.; Methodology: Y.M., A.M.; Validation: Y.M., A.M.; Formal analysis: Y.M.; Investigation: Y.M., S.S., J.W., N.E., K.L.H., A.M.; Data curation: Y.M., A.M.; Writing - original draft: A.M.; Writing - review & editing: Y.M., K.L.H., A.M.; Visualization: Y.M., K.L.H., A.M.; Supervision: A.M.; Project administration: A.M.; Funding acquisition: A.M.
Funding
This work was supported by the National Institute of Child Health and Human Development (R00HD098918 and DP2115157 to A.M.). Y.M. is supported by a Japan Society for the Promotion of Science Overseas Research Fellowship and a Duke University Regeneration Center (DRC) Post-doctoral Research Award to Accelerate Career Independence. Deposited in PMC for release after 12 months.
Data availability
All relevant data can be found within the article and its supplementary information.
