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BMP signaling is required for septation of the outflow tract of the mammalian heart.
- Source :
-
Development (Cambridge, England) [Development] 2003 Jan; Vol. 130 (1), pp. 209-20. - Publication Year :
- 2003
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence
Animals
Aorta, Thoracic abnormalities
Aorta, Thoracic embryology
Aorta, Thoracic metabolism
Bone Morphogenetic Protein Receptors, Type II
Bone Morphogenetic Proteins genetics
Fetal Death genetics
Gastrula
Gene Dosage
Heart Defects, Congenital
Heart Valves abnormalities
Heart Valves embryology
Mammals
Mice
Mice, Knockout
Molecular Sequence Data
Protein Serine-Threonine Kinases genetics
Ribs abnormalities
Sequence Homology, Amino Acid
Signal Transduction
Truncus Arteriosus, Persistent genetics
Bone Morphogenetic Proteins metabolism
Heart Septum embryology
Heart Septum metabolism
Heart Valves metabolism
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0950-1991
- Volume :
- 130
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 12441304
- Full Text :
- https://doi.org/10.1242/dev.00181