An Essential Role of Bmp4 in the Atrioventricular Septation of the Mouse Heart

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2003 Sep 17

PMID 12975322

Citations 211

Authors

Kai Jiao

Holger Kulessa

Kevin Tompkins

Yingna Zhou

Lorene Batts

H Scott Baldwin

Brigid L M Hogan

Affiliations

Soon will be listed here.

Abstract

Proper septation and valvulogenesis during cardiogenesis depend on interactions between the myocardium and the endocardium. By combining use of a hypomorphic Bone morphogenetic protein 4 (Bmp4) allele with conditional gene inactivation, we here identify Bmp4 as a signal from the myocardium directly mediating atrioventricular septation. Defects in this process cause one of the most common human congenital heart abnormalities, atrioventricular canal defect (AVCD). The spectrum of defects obtained through altering Bmp4 expression in the myocardium recapitulates the range of AVCDs diagnosed in patients, thus providing a useful genetic model with AVCD as the primary defect.

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References

Lakkis M, Epstein J . Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development. 1998; 125(22):4359-67. DOI: 10.1242/dev.125.22.4359. View

Webb S, Brown N, Anderson R . Cardiac morphology at late fetal stages in the mouse with trisomy 16: consequences for different formation of the atrioventricular junction when compared to humans with trisomy 21. Cardiovasc Res. 1997; 34(3):515-24. DOI: 10.1016/s0008-6363(97)00064-3. View

Lawson K, Dunn N, Roelen B, Zeinstra L, Davis A, Wright C . Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev. 1999; 13(4):424-36. PMC: 316469. DOI: 10.1101/gad.13.4.424. View

Neuhaus H, Rosen V, Thies R . Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech Dev. 1999; 80(2):181-4. DOI: 10.1016/s0925-4773(98)00221-4. View

Boyer A, Ayerinskas I, Vincent E, McKinney L, Weeks D, Runyan R . TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol. 1999; 208(2):530-45. DOI: 10.1006/dbio.1999.9211. View

Weaver M, Yingling J, Dunn N, Bellusci S, Hogan B . Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. Development. 1999; 126(18):4005-15. DOI: 10.1242/dev.126.18.4005. View

Nakajima Y, Yamagishi T, HOKARI S, Nakamura H . Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP). Anat Rec. 2000; 258(2):119-27. DOI: 10.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U. View

Galvin K, Donovan M, Lynch C, Meyer R, Paul R, Lorenz J . A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet. 2000; 24(2):171-4. DOI: 10.1038/72835. View

Wang Q, Sigmund C, Lin J . Identification of cis elements in the cardiac troponin T gene conferring specific expression in cardiac muscle of transgenic mice. Circ Res. 2000; 86(4):478-84. DOI: 10.1161/01.res.86.4.478. View

10.

Tevosian S, Deconinck A, Tanaka M, Schinke M, Litovsky S, Izumo S . FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell. 2000; 101(7):729-39. DOI: 10.1016/s0092-8674(00)80885-5. View

11.

Camenisch T, Spicer A, Brehm-Gibson T, Biesterfeldt J, Augustine M, Calabro Jr A . Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest. 2000; 106(3):349-60. PMC: 314332. DOI: 10.1172/JCI10272. View

12.

Kirchhoff S, Kim J, Hagendorff A, Thonnissen E, Kruger O, Lamers W . Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43 double-deficient mice. Circ Res. 2000; 87(5):399-405. DOI: 10.1161/01.res.87.5.399. View

13.

Waller 3rd B, McQuinn T, Phelps A, Markwald R, Lo C, Thompson R . Conotruncal anomalies in the trisomy 16 mouse: an immunohistochemical analysis with emphasis on the involvement of the neural crest. Anat Rec. 2000; 260(3):279-93. DOI: 10.1002/1097-0185(20001101)260:3<279::AID-AR65>3.0.CO;2-2. View

14.

Marino B, Digilio M . Congenital heart disease and genetic syndromes: specific correlation between cardiac phenotype and genotype. Cardiovasc Pathol. 2001; 9(6):303-15. DOI: 10.1016/s1054-8807(00)00050-8. View

15.

Wang Q, Reiter R, Huang Q, Jin J, Lin J . Comparative studies on the expression patterns of three troponin T genes during mouse development. Anat Rec. 2001; 263(1):72-84. DOI: 10.1002/ar.1078. View

16.

Pierpont M, Markwald R, Lin A . Genetic aspects of atrioventricular septal defects. Am J Med Genet. 2001; 97(4):289-96. View

17.

Bartram U, Molin D, Wisse L, Mohamad A, Sanford L, Doetschman T . Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice. Circulation. 2001; 103(22):2745-52. DOI: 10.1161/01.cir.103.22.2745. View

18.

Abdelwahid E, Rice D, Pelliniemi L, Jokinen E . Overlapping and differential localization of Bmp-2, Bmp-4, Msx-2 and apoptosis in the endocardial cushion and adjacent tissues of the developing mouse heart. Cell Tissue Res. 2001; 305(1):67-78. DOI: 10.1007/s004410100399. View

19.

von Bubnoff A, Cho K . Intracellular BMP signaling regulation in vertebrates: pathway or network?. Dev Biol. 2002; 239(1):1-14. DOI: 10.1006/dbio.2001.0388. View

20.

Kulessa H, Hogan B . Generation of a loxP flanked bmp4loxP-lacZ allele marked by conditional lacZ expression. Genesis. 2002; 32(2):66-8. DOI: 10.1002/gene.10032.abs. View