The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expression.
The Zfp36l1 gene encodes a zinc finger-containing mRNA binding protein implicated in the posttranscriptional control of gene expression. Mouse embryos homozygous for a targeted mutation in the Zfp36l1 locus died mid-gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, there was a failure of the extraembryonic mesoderm to invaginate the trophoblast layer. The phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)-A in the embryos and in embryonic fibroblasts cultured under conditions of both normoxia and hypoxia. VEGF-A overproduction by embryonic fibroblasts was not a consequence of changes in Vegf-a mRNA stability; instead, we observed enhanced association with polyribosomes, suggesting Zfp36l1 influences translational regulation. These data implicate Zfp36l1as a negative regulator of Vegf-a gene activity during development.
Bell
Sarah E
SE
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, United Kingdom. sarah-e.bell@bbsrc.ac.uk
Sanchez
Maria Jose
MJ
Spasic-Boskovic
Olivera
O
Santalucia
Tomas
T
Gambardella
Laure
L
Burton
Graham J
GJ
Murphy
John J
JJ
Norton
John D
JD
Clark
Andrew R
AR
Turner
Martin
M
D000818:Animals; D051817:Butyrate Response Factor 1; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011132:Polyribosomes / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D051817:Butyrate Response Factor 1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; C488431:Zfp36l1 protein, mouse