The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1

J Biol Chem. 2010 Feb 26;285(9):6770-80. doi: 10.1074/jbc.M109.082347. Epub 2009 Dec 21.


Nedd4 (Nedd4-1) is a Hect domain E3 ubiquitin ligase that also contains a C2 domain and three WW domains. Despite numerous in vitro studies, its biological function in vivo is not well understood. Here we show that disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities. Quantitative mass spectrometry and immunoblot analyses of lysates from the wild type and knock-out mouse embryonic fibroblasts to identify Nedd4-1 in vivo targets revealed dramatically increased amounts of thrombospondin-1 (Tsp-1) in the knock-out mouse embryonic fibroblasts and embryos. Tsp-1 is an inhibitor of angiogenesis, and its elevated level was mediated primarily by enhanced transcription. Interestingly, the administration of aspirin (an inhibitor of Tsp-1) to the pregnant heterozygote mothers led to a reduction in Tsp-1 levels and a substantial rescue of the embryonic lethality. These results suggest that Nedd4-1 is a suppressor of Tsp1 and that increased levels of Tsp-1 in the Nedd4-1 knock-out mice may have contributed to the developmental defect observed in the embryos.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspirin / pharmacology
  • Endosomal Sorting Complexes Required for Transport / deficiency
  • Endosomal Sorting Complexes Required for Transport / physiology*
  • Female
  • Fibroblasts
  • Heart / embryology
  • Heart / growth & development*
  • Heart Defects, Congenital / genetics
  • Mice
  • Mice, Knockout
  • Nedd4 Ubiquitin Protein Ligases
  • Pregnancy
  • Thrombospondin 1 / antagonists & inhibitors*
  • Thrombospondin 1 / drug effects
  • Thrombospondin 1 / genetics
  • Transcription, Genetic
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / physiology*


  • Endosomal Sorting Complexes Required for Transport
  • Thrombospondin 1
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4l protein, mouse
  • Ubiquitin-Protein Ligases
  • Aspirin