Nkx2-5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo.
Recent studies support the existence of a common progenitor for the cardiac and endothelial cell lineages, but the underlying transcriptional networks responsible for specification of these cell fates remain unclear. Here we demonstrated that Ets-related protein 71 (Etsrp71), a newly discovered ETS family transcription factor, was a novel downstream target of the homeodomain protein, Nkx2-5. Using genetic mouse models and molecular biological techniques, we demonstrated that Nkx2-5 binds to an evolutionarily conserved Nkx2-5 response element in the Etsrp71 promoter and induces the Etsrp71 gene expression in vitro and in vivo. Etsrp71 was transiently expressed in the endocardium/endothelium of the developing embryo (E7.75-E9.5) and was extinguished during the latter stages of development. Using a gene disruption strategy, we found that Etsrp71 mutant embryos lacked endocardial/endothelial lineages and were nonviable. Moreover, using transgenic technologies and transcriptional and chromatin immunoprecipitation (ChIP) assays, we further established that Tie2 is a direct downstream target of Etsrp71. Collectively, our results uncover a novel functional role for Nkx2-5 and define a transcriptional network that specifies an endocardial/endothelial fate in the developing heart and embryo.
Ferdous
Anwarul
A
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75244, USA.
Caprioli
Arianna
A
Iacovino
Michelina
M
Martin
Cindy M
CM
Morris
Jesse
J
Richardson
James A
JA
Latif
Shuaib
S
Hammer
Robert E
RE
Harvey
Richard P
RP
Olson
Eric N
EN
Kyba
Michael
M
Garry
Daniel J
DJ
D000818:Animals; D019070:Cell Lineage; D004699:Endocardium / Q000196:embryology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000196:embryology* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation
C503994:ER71 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D042787:Receptor, TIE-2