title: Nkx2-5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75244, USA.
authors.forename: Anwarul
authors.initials: A
authors.lastname: Ferdous
authors.forename: Arianna
authors.initials: A
authors.lastname: Caprioli
authors.forename: Michelina
authors.initials: M
authors.lastname: Iacovino
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Martin
authors.forename: Jesse
authors.initials: J
authors.lastname: Morris
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Shuaib
authors.initials: S
authors.lastname: Latif
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Garry
mesh_terms: 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
chemical_list: 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