VGLL4 plays a critical role in heart valve development and homeostasis

PLoS Genet. 2019 Feb 21;15(2):e1007977. doi: 10.1371/journal.pgen.1007977. eCollection 2019 Feb.


Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Proliferation
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Developmental
  • Gene Knockout Techniques
  • Heart Valves / cytology
  • Heart Valves / growth & development*
  • Heart Valves / metabolism
  • Homeostasis
  • Hypertrophy, Left Ventricular / genetics*
  • Hypertrophy, Left Ventricular / veterinary
  • Mice
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*


  • Transcription Factors
  • VGLL4 protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases

Grant support

This work was supported by National Key Research and Development Program of China (2017YFA0103601 to LZ), National Natural Science Foundation of China (No. 31530043 to LZ, No. 31625017 to LZ), “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDB19000000 to LZ), the Youth Innovation Promotion Association CAS to ZW. Shanghai Leading Talents Program to LZ, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020204 to BZ, XDB19000000 to BZ), National Science Foundation of China (31730112 to BZ, 91639302 to BZ, 31625019 to BZ, 91849202 to BZ, 81761138040 to BZ) China Postdoctoral Science Foundation (BX201700264 to JL, 2017M611634 to WY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.