Munjal, Akankshi; Hannezo, Edouard ISTA ; Tsai, Tony Y.C.; Mitchison, Timothy J.; Megason, Sean G.
How tissues acquire complex shapes is a fundamental question in biology and regenerative medicine. Zebrafish semicircular canals form from invaginations in the otic epithelium (buds) that extend and fuse to form the hubs of each canal. We find that conventional actomyosin-driven behaviors are not required. Instead, local secretion of hyaluronan, made by the enzymes uridine 5′-diphosphate dehydrogenase (ugdh) and hyaluronan synthase 3 (has3), drives canal morphogenesis. Charged hyaluronate polymers osmotically swell with water and generate isotropic extracellular pressure to deform the overlying epithelium into buds. The mechanical anisotropy needed to shape buds into tubes is conferred by a polarized distribution of actomyosin and E-cadherin-rich membrane tethers, which we term cytocinches. Most work on tissue morphogenesis ascribes actomyosin contractility as the driving force, while the extracellular matrix shapes tissues through differential stiffness. Our work inverts this expectation. Hyaluronate pressure shaped by anisotropic tissue stiffness may be a widespread mechanism for powering morphological change in organogenesis and tissue engineering.
We thank Ian Swinburne, Sandy Nandagopal, and Toru Kawanishi for support, discussions, and reagents. We thank Vanessa Barone, Joseph Nasser, and members of the Megason lab for useful comments on the manuscript and general feedback. We are grateful to the Heisenberg and Knaut labs for transgenic fish. Diagrams on the right in the graphical abstract were created using BioRender. This work was supported by NIH R01DC015478 and NIH R01GM107733 to S.G.M. A.M. was supported by Human Frontiers Science Program LTF and NIH K99HD098918.
Munjal A, Hannezo EB, Tsai TYC, Mitchison TJ, Megason SG. Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis. Cell. 2021;184(26):6313-6325.e18. doi:10.1016/j.cell.2021.11.025
Munjal, A., Hannezo, E. B., Tsai, T. Y. C., Mitchison, T. J., & Megason, S. G. (2021). Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis. Cell. Elsevier ; Cell Press. https://doi.org/10.1016/j.cell.2021.11.025
Munjal, Akankshi, Edouard B Hannezo, Tony Y.C. Tsai, Timothy J. Mitchison, and Sean G. Megason. “Extracellular Hyaluronate Pressure Shaped by Cellular Tethers Drives Tissue Morphogenesis.” Cell. Elsevier ; Cell Press, 2021. https://doi.org/10.1016/j.cell.2021.11.025.
A. Munjal, E. B. Hannezo, T. Y. C. Tsai, T. J. Mitchison, and S. G. Megason, “Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis,” Cell, vol. 184, no. 26. Elsevier ; Cell Press, p. 6313–6325.e18, 2021.
Munjal A, Hannezo EB, Tsai TYC, Mitchison TJ, Megason SG. 2021. Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis. Cell. 184(26), 6313–6325.e18.
Munjal, Akankshi, et al. “Extracellular Hyaluronate Pressure Shaped by Cellular Tethers Drives Tissue Morphogenesis.” Cell, vol. 184, no. 26, Elsevier ; Cell Press, 2021, p. 6313–6325.e18, doi:10.1016/j.cell.2021.11.025.
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