Copyright © 2004, European Society of Cardiology
Roles of forkhead transcription factor Foxc2 (MFH-1) and endothelin receptor A in cardiovascular morphogenesis
aDepartment of Biochemistry, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
bDepartment of Gynecology and Obstetrics, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
cDepartment of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Hamamatsu 431-3192, Japan
dDepartment of Molecular Genetics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA
* Corresponding author. Tel.: +81 53 435 2325; fax: +81 53 435 2369. Email address: nmiura{at}hama-med.ac.jp
Objective: Foxc2/MFH-1 is a member of the forkhead family of transcription factors and Foxc2-deficient mice exhibit aortic arch anomalies (type B interruption of the aortic arch). Endothelin receptor type-A (ETA) is one of the two known endothelin receptors that belong to the G-protein-coupled receptor family. ETA-deficient mice show defects in the great arteries, primarily type B interruption of the aortic arch. Based on similar phenotypes in the cardiovascular system of Foxc2- and ETA-deficient mice, we investigated whether Foxc2 and ETA have a close relationship in aortic arch patterning.
Methods: The Foxc2 and ETA homozygotes were obtained by crossing the Foxc2 and ETA heterozygotes, respectively. The double Foxc2/ETA homozygotes were obtained by crossing the double Foxc2/ETA heterozygotes.
Results: We investigated the expression of ETA in Foxc2-null mice and the expression of Foxc2 in ETA-null mice and found that the absence of either Foxc2 or ETA had no effect on the expression of the other. Next, we analyzed mice lacking both Foxc2 and ETA to examine the relationship between Foxc2 and ETA on aortic arch patterning in vivo. We found that the majority of Foxc2/ETA double-mutant embryos died around 11.5 dpc and that all surviving mice had persistent truncus arteriosus.
Conclusions: The results suggest that Foxc2- and ETA-expressing cells additively form the aorticopulmonary septum.
KEYWORDS Foxc2; Arteries; Developmental biology; Gene expression; Heart failure
Abbreviations: ETA, endothelin receptor A • ET-1, endothelin-1 • IAA, interruption of the aortic arch • MFH-1, mesenchyme forkhead-1 • PTA, persistent truncus arteriosus • VSD, ventricular septal defect