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PMID:20026598

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Citation

Fouladkou, F, Lu, C, Jiang, C, Zhou, L, She, Y, Walls, JR, Kawabe, H, Brose, N, Henkelman, RM, Huang, A, Bruneau, BG and Rotin, D (2010) The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1. J. Biol. Chem. 285:6770-80

Abstract

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.

Links

PubMed PMC2825471 Online version:10.1074/jbc.M109.082347

Keywords

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; Pregnancy; Thrombospondin 1/antagonists & inhibitors; Thrombospondin 1/drug effects; Thrombospondin 1/genetics; Transcription, Genetic; Ubiquitin-Protein Ligases/deficiency; Ubiquitin-Protein Ligases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TSP1

acts_upstream_of_or_within

GO:0003197: endocardial cushion development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97297

P

  • results_in_development_of:(EMAPA:16696)

Seeded From UniProt

complete

MOUSE:TSP1

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97297

P

Seeded From UniProt

complete

MOUSE:TSP1

acts_upstream_of_or_within

GO:0048514: blood vessel morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97297

P

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

  • has_input:(MGI:MGI:98737)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003197: endocardial cushion development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

  • results_in_development_of:(EMAPA:16696)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003197: endocardial cushion development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98737

P

  • results_in_development_of:(EMAPA:16696)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98737

P

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0048514: blood vessel morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0048514: blood vessel morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98737

P

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003197: endocardial cushion development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98737

P

results_in_development_of:(EMAPA:16696)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0048514: blood vessel morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98737

P

has_participant:(EMAPA:16240)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0048514: blood vessel morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

has_participant:(EMAPA:16240)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98737

P

has_participant:(EMAPA:16346)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003197: endocardial cushion development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

results_in_development_of:(EMAPA:16696)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

has_regulation_target:(MGI:MGI:98737)

Seeded From UniProt

complete

MOUSE:NEDD4

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3799317

P

has_participant:(EMAPA:16346)

Seeded From UniProt

complete


See also

References

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