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RESEARCH PAPER

Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1

¹ INSERM U636, Centre de Biochimie, Faculté des Sciences, 06108 Nice, France; ² Medizinische Klinik und Poliklinik, and ³ Institut für Physiologie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; ⁴ Institute of Molecular Biotechnology, 07745 Jena, Germany

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 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.

[Keywords: Vasculogenesis; neurotrophin receptor; transcription factor; transgenic mice; Wilms' tumor; epicardium]

Received April 7, 2005; revised version accepted August 25, 2005.

Corresponding authors.

⁵ These authors contributed equally to this work.

⁷ E-MAIL schedl{at}unice.fr; FAX 33-04-92-07-6402.

⁶ E-MAIL holger.scholz{at}charite.de; FAX 49-30-450-528972.

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