title: Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1.
abstract: The formation of intramyocardial blood vessels is critical for normal heart development and tissue repair after infarction. We report here expression of the Wilms' tumor gene-1, Wt1, in coronary vessels, which could contribute to the defective cardiac vascularization in Wt1-/- mice. Furthermore, the high-affinity neurotrophin receptor TrkB, which is expressed in the epicardium and subepicardial blood vessels, was nearly absent from Wt1-deficient hearts. Activation of Wt1 in an inducible cell line significantly enhanced TrkB expression. The promoter of NTRK2, the gene encoding TrkB, was stimulated approximately 10-fold by transient cotransfection of a Wt1 expression construct. The critical DNA-binding site for activation of the NTRK2 promoter by Wt1 was delineated by DNase I footprint analysis and electrophoretic mobility shift assay. Transgenic experiments revealed that the identified Wt1 consensus motif in the NTRK2 promoter was necessary to direct expression of a reporter gene to the epicardium and the developing vasculature of embryonic mouse hearts. Finally, mice with a disrupted Ntrk2 gene lacked a significant proportion of their intramyocardial blood vessels. These findings demonstrate that transcriptional activation of the TrkB neurotrophin receptor gene by the Wilms' tumor suppressor Wt1 is a crucial mechanism for normal vascularization of the developing heart.
authors.affiliation: INSERM U636, Centre de Biochimie, Faculté des Sciences, 06108 Nice, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wagner
authors.forename: Kay-Dietrich
authors.initials: KD
authors.lastname: Wagner
authors.forename: Heinz
authors.initials: H
authors.lastname: Theres
authors.forename: Christoph
authors.initials: C
authors.lastname: Englert
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.forename: Holger
authors.initials: H
authors.lastname: Scholz
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D018983:DNA Footprinting; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006321:Heart / Q000196:embryology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB
chemical_list: D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D011505:Protein-Tyrosine Kinases; D025721:WT1 Proteins; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB