Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1.
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.
Wagner
Nicole
N
INSERM U636, Centre de Biochimie, Faculté des Sciences, 06108 Nice, France.
Wagner
Kay-Dietrich
KD
Theres
Heinz
H
Englert
Christoph
C
Schedl
Andreas
A
Scholz
Holger
H
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
D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D011505:Protein-Tyrosine Kinases; D025721:WT1 Proteins; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB