ZFIN ID: ZDB-PUB-190212-6
MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis
Moro, A., Driscoll, T.P., Boraas, L.C., Armero, W., Kasper, D.M., Baeyens, N., Jouy, C., Mallikarjun, V., Swift, J., Ahn, S.J., Lee, D., Zhang, J., Gu, M., Gerstein, M., Schwartz, M., Nicoli, S.
Date: 2019
Source: Nature cell biology   21(3): 348-358 (Journal)
Registered Authors: Ahn, Sang Jung, Boraas, Liana, Kasper, Dionna, Moro, Albertomaria, Nicoli, Stefania
Keywords: none
MeSH Terms:
  • 3' Untranslated Regions
  • Animal Fins/metabolism
  • Animals
  • Cell Line
  • Cells, Cultured
  • Endothelial Cells/metabolism*
  • Extracellular Matrix Proteins/genetics
  • Extracellular Matrix Proteins/metabolism
  • Fibroblasts/metabolism*
  • Gene Expression Regulation*
  • Homeostasis/genetics
  • Humans
  • Mice, Inbred C57BL
  • MicroRNAs/genetics*
  • MicroRNAs/metabolism
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 30742093 Full text @ Nat. Cell Biol.
Vertebrate tissues exhibit mechanical homeostasis, showing stable stiffness and tension over time and recovery after changes in mechanical stress. However, the regulatory pathways that mediate these effects are unknown. A comprehensive identification of Argonaute 2-associated microRNAs and mRNAs in endothelial cells identified a network of 122 microRNA families that target 73 mRNAs encoding cytoskeletal, contractile, adhesive and extracellular matrix (CAM) proteins. The level of these microRNAs increased in cells plated on stiff versus soft substrates, consistent with homeostasis, and suppressed targets via microRNA recognition elements within the 3' untranslated regions of CAM mRNAs. Inhibition of DROSHA or Argonaute 2, or disruption of microRNA recognition elements within individual target mRNAs, such as connective tissue growth factor, induced hyper-adhesive, hyper-contractile phenotypes in endothelial and fibroblast cells in vitro, and increased tissue stiffness, contractility and extracellular matrix deposition in the zebrafish fin fold in vivo. Thus, a network of microRNAs buffers CAM expression to mediate tissue mechanical homeostasis.