|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
doi: 10.1242/10.1242/dev.00181
DEVELOPMENT AND DISEASE |
1 Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA
90095, USA
2 Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA 90095,
USA
3 Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA 90095,
USA
4 Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, CA
90095, USA
5 Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA
90095, USA
* Author for correspondence (e-mail: klyons{at}mednet.ucla.edu)
Accepted 1 October 2002
Bone morphogenetic proteins (BMPs) constitute a family of 
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
E2 mutants makes this strain a key murine
model to understand the embryonic defects of persistent truncus arteriosus and
impaired semilunar valve formation in humans.
Key words: Bone morphogenetic protein, Endocardial cushion, Outflow tract septation, Persistent truncus arteriosus, Hypomorph, Semilunar valve
This article has been cited by other articles:
|
|
 |
|
  K.-H. Hong, Y. J. Lee, E. Lee, S. O. Park, C. Han, H. Beppu, E. Li, M. K. Raizada, K. D. Bloch, and S. P. Oh Genetic Ablation of the Bmpr2 Gene in Pulmonary Endothelium Is Sufficient to Predispose to Pulmonary Arterial Hypertension Circulation, August 12, 2008; 118(7): 722 - 730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kaneko, X. Li, X. Zhang, J. J. Lamberti, S. W. Jamieson, and P. A. Thistlethwaite Endothelial Expression of Bone Morphogenetic Protein Receptor Type 1a is Required for Atrioventricular Valve Formation. Ann. Thorac. Surg., June 1, 2008; 85(6): 2090 - 2098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Frank, J. Lowery, L. Anderson, M. Brink, J. Reese, and M. de Caestecker Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L98 - L109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. SHAO, Z. A. ALY, C.-F. LAI, S.-L. CHENG, J. CAI, E. HUANG, A. BEHRMANN, and D. A. TOWLER Vascular Bmp Msx2 Wnt Signaling and Oxidative Stress in Arterial Calcification Ann. N.Y. Acad. Sci., November 1, 2007; 1117(1): 40 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liu, J. Wang, B. Kinzel, M. Mueller, X. Mao, R. Valdez, Y. Liu, and E. Li Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity Blood, September 1, 2007; 110(5): 1502 - 1510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Van de Putte, A. Francis, L. Nelles, L. A. van Grunsven, and D. Huylebroeck Neural crest-specific removal of Zfhx1b in mouse leads to a wide range of neurocristopathies reminiscent of Mowat-Wilson syndrome Hum. Mol. Genet., June 15, 2007; 16(12): 1423 - 1436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ai, X. Fu, J. Wang, M.-F. Lu, L. Chen, A. Baldini, W. H. Klein, and J. F. Martin Canonical Wnt signaling functions in second heart field to promote right ventricular growth PNAS, May 29, 2007; 104(22): 9319 - 9324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. van Wijk, A. F.M. Moorman, and M. J.B. van den Hoff Role of bone morphogenetic proteins in cardiac differentiation Cardiovasc Res, May 1, 2007; 74(2): 244 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ikeya, M. Kawada, H. Kiyonari, N. Sasai, K. Nakao, Y. Furuta, and Y. Sasai Essential pro-Bmp roles of crossveinless 2 in mouse organogenesis Development, November 15, 2006; 133(22): 4463 - 4473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. W. Morrell Pulmonary Hypertension Due to BMPR2 Mutation: A New Paradigm for Tissue Remodeling? Proceedings of the ATS, November 1, 2006; 3(8): 680 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ihida-Stansbury, D. M. McKean, K. B. Lane, J. E. Loyd, L. A. Wheeler, N. W. Morrell, and P. L. Jones Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L694 - L702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Bosman, K. A. Lawson, J. Debruyn, L. Beek, A. Francis, L. Schoonjans, D. Huylebroeck, and A. Zwijsen Smad5 determines murine amnion fate through the control of bone morphogenetic protein expression and signalling levels Development, September 1, 2006; 133(17): 3399 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Park, K. Lavine, Y. Mishina, C.-X. Deng, D. M. Ornitz, and K. Choi Bone morphogenetic protein receptor 1A signaling is dispensable for hematopoietic development but essential for vessel and atrioventricular endocardial cushion formation Development, September 1, 2006; 133(17): 3473 - 3484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Park, L. A. Ogden, A. Talbot, S. Evans, C.-L. Cai, B. L. Black, D. U. Frank, and A. M. Moon Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling Development, June 15, 2006; 133(12): 2419 - 2433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yang, C.-L. Cai, L. Lin, Y. Qyang, C. Chung, R. M. Monteiro, C. L. Mummery, G. I. Fishman, A. Cogen, and S. Evans Isl1Cre reveals a common Bmp pathway in heart and limb development. Development, April 1, 2006; 133(8): 1575 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ishii, J. Han, H.-Y. Yen, H. M. Sucov, Y. Chai, and R. E. Maxson Jr Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest Development, November 15, 2005; 132(22): 4937 - 4950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. K. P. Wong, J. A. Knowles, and J. H. Morse Bone Morphogenetic Protein Receptor Type II C-Terminus Interacts with c-Src: Implication for a Role in Pulmonary Arterial Hypertension Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 438 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Gaussin, G. E. Morley, L. Cox, A. Zwijsen, K. M. Vance, L. Emile, Y. Tian, J. Liu, C. Hong, D. Myers, et al. Alk3/Bmpr1a Receptor Is Required for Development of the Atrioventricular Canal Into Valves and Annulus Fibrosus Circ. Res., August 5, 2005; 97(3): 219 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Takeuchi, M. Mileikovskaia, K. Koshiba-Takeuchi, A. B. Heidt, A. D. Mori, E. P. Arruda, M. Gertsenstein, R. Georges, L. Davidson, R. Mo, et al. Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development Development, May 15, 2005; 132(10): 2463 - 2474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Machado, V. James, M. Southwood, R. E. Harrison, C. Atkinson, S. Stewart, N. W. Morrell, R. C. Trembath, and M. A. Aldred Investigation of Second Genetic Hits at the BMPR2 Locus as a Modulator of Disease Progression in Familial Pulmonary Arterial Hypertension Circulation, February 8, 2005; 111(5): 607 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Li, Y. Li, W. Du, L. Zhang, S. Yu, Y. Dai, C. Zhao, and N. Li Aberrant Gene Expression in Organs of Bovine Clones That Die Within Two Days after Birth Biol Reprod, February 1, 2005; 72(2): 258 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Harrison, R. Berger, S. G. Haworth, R. Tulloh, C. J. Mache, N. W. Morrell, M. A. Aldred, and R. C. Trembath Transforming Growth Factor-{beta} Receptor Mutations and Pulmonary Arterial Hypertension in Childhood Circulation, February 1, 2005; 111(4): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Coles, J. Christiansen, A. Economou, M. Bronner-Fraser, and D. G. Wilkinson A vertebrate crossveinless 2 homologue modulates BMP activity and neural crest cell migration Development, November 1, 2004; 131(21): 5309 - 5317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Monteiro, S. M. C. de Sousa Lopes, O. Korchynskyi, P. t. Dijke, and C. L. Mummery Spatio-temporal activation of Smad1 and Smad5 in vivo: monitoring transcriptional activity of Smad proteins J. Cell Sci., September 15, 2004; 117(20): 4653 - 4663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Armstrong and J. Bischoff Heart Valve Development: Endothelial Cell Signaling and Differentiation Circ. Res., September 3, 2004; 95(5): 459 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.E. Roberts, J.J. McElroy, W.P.K. Wong, E. Yen, A. Widlitz, R.J. Barst, J.A. Knowles, and J.H. Morse BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease Eur. Respir. J., September 1, 2004; 24(3): 371 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sock, S. D. Rettig, J. Enderich, M. R. Bosl, E. R. Tamm, and M. Wegner Gene Targeting Reveals a Widespread Role for the High-Mobility-Group Transcription Factor Sox11 in Tissue Remodeling Mol. Cell. Biol., August 1, 2004; 24(15): 6635 - 6644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Kaartinen, M. Dudas, A. Nagy, S. Sridurongrit, M. M. Lu, and J. A. Epstein Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells Development, July 15, 2004; 131(14): 3481 - 3490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Newman, R. C. Trembath, J. A. Morse, E. Grunig, J. E. Loyd, S. Adnot, F. Coccolo, C. Ventura, J. A. Phillips III, J. A. Knowles, et al. Genetic basis of pulmonary arterial hypertension: Current understanding and future directions J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 33S - 39S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Stottmann, M. Choi, Y. Mishina, E. N. Meyers, and J. Klingensmith BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium Development, May 1, 2004; 131(9): 2205 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Plageman Jr. and K. E. Yutzey Differential Expression and Function of Tbx5 and Tbx20 in Cardiac Development J. Biol. Chem., April 30, 2004; 279(18): 19026 - 19034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. West, K. Fagan, W. Steudel, B. Fouty, K. Lane, J. Harral, M. Hoedt-Miller, Y. Tada, J. Ozimek, R. Tuder, et al. Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth Muscle Circ. Res., April 30, 2004; 94(8): 1109 - 1114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, J. Selever, D. Wang, M.-F. Lu, K. A. Moses, R. J. Schwartz, and J. F. Martin Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodeling PNAS, March 30, 2004; 101(13): 4489 - 4494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Gruber and J. A. Epstein Development Gone Awry: Congenital Heart Disease Circ. Res., February 20, 2004; 94(3): 273 - 283. [Abstract] [Full Text] [PDF]
|
|
