BMP signaling is required for septation of the outflow tract of the mammalian heart.
Bone morphogenetic proteins (BMPs) constitute a family of approximately 20 growth factors involved in a tremendous variety of embryonic inductive processes. BMPs elicit dose-dependent effects on patterning during gastrulation and gradients of BMP activity are thought to be established through regulation of the relative concentrations of BMP receptors, ligands and antagonists. We tested whether later developmental events also are sensitive to reduced levels of BMP signaling. We engineered a knockout mouse that expresses a BMP type II receptor that lacks half of the ligand-binding domain. This altered receptor is expressed at levels comparable with the wild-type allele, but has reduced signaling capability. Unlike Bmpr2-null mice, mice homozygous for this hypomorphic receptor undergo normal gastrulation, providing genetic evidence of the dose-dependent effects of BMPs during mammalian development. Mutants, however, die at midgestation with cardiovascular and skeletal defects, demonstrating that the development of these tissues requires wild-type levels of BMP signaling. The most striking defects occur in the outflow tract of the heart, with absence of septation of the conotruncus below the valve level and interrupted aortic arch, a phenotype known in humans as persistent truncus arteriosus (type A4). In addition, semilunar valves do not form in mutants, while the atrioventricular valves appear unaffected. Abnormal septation of the heart and valve anomalies are the most frequent forms of congenital cardiac defects in humans; however, most mouse models display broad defects throughout cardiac tissues. The more restricted spectrum of cardiac anomalies in Bmpr2(deltaE2) mutants makes this strain a key murine model to understand the embryonic defects of persistent truncus arteriosus and impaired semilunar valve formation in humans.
Délot
Emmanuèle C
EC
Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Bahamonde
Matthew E
ME
Zhao
Manxu
M
Lyons
Karen M
KM
D000595:Amino Acid Sequence; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D005313:Fetal Death / Q000235:genetics; D005775:Gastrula; D018628:Gene Dosage; D006330:Heart Defects, Congenital; D006346:Heart Septum / Q000196:embryology* / Q000378:metabolism*; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism*; D008322:Mammals; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012272:Ribs / Q000002:abnormalities; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014339:Truncus Arteriosus, Persistent / Q000235:genetics
D019485:Bone Morphogenetic Proteins; D017346:Protein Serine-Threonine Kinases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II