Genetic Interaction Between Bmp2 and Bmp4 Reveals Shared Functions During Multiple Aspects of Mouse Organogenesis

Overview

Journal Mech Dev

Publisher Elsevier

Specialties Biology
Cell Biology
Reproductive Medicine

Date 2009 Jan 1

PMID 19116164

Citations 30

Authors

Devorah C Goldman

Nathan Donley

Jan L Christian

Affiliations

Soon will be listed here.

Abstract

Vertebrate Bmp2 and Bmp4 diverged from a common ancestral gene and encode closely related proteins. Mice homozygous for null mutations in either gene show early embryonic lethality, thereby precluding analysis of shared functions. In the current studies, we present phenotypic analysis of compound mutant mice heterozygous for a null allele of Bmp2 in combination with null or hypomorphic alleles of Bmp4. Whereas mice lacking a single copy of Bmp2 or Bmp4 are viable and have subtle developmental defects, compound mutants show embryonic and postnatal lethality due to defects in multiple organ systems including the allantois, placental vasculature, ventral body wall, skeleton, eye and heart. Within the heart, BMP2 and BMP4 function coordinately to direct normal lengthening of the outflow tract, proper positioning of the outflow vessels, and septation of the atria, ventricle and atrioventricular canal. Our results identify numerous BMP4-dependent developmental processes that are also very sensitive to BMP2 dosage, thus revealing novel functions of Bmp2.

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References

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

Ying Y, Qi X, Zhao G . Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc Natl Acad Sci U S A. 2001; 98(14):7858-62. PMC: 35432. DOI: 10.1073/pnas.151242798. View

Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin H . An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev. 2003; 17(19):2362-7. PMC: 218073. DOI: 10.1101/gad.1124803. View

Rivera-Feliciano J, Tabin C . Bmp2 instructs cardiac progenitors to form the heart-valve-inducing field. Dev Biol. 2006; 295(2):580-8. PMC: 2680002. DOI: 10.1016/j.ydbio.2006.03.043. View

Klaus A, Saga Y, Taketo M, Tzahor E, Birchmeier W . Distinct roles of Wnt/beta-catenin and Bmp signaling during early cardiogenesis. Proc Natl Acad Sci U S A. 2007; 104(47):18531-6. PMC: 2141811. DOI: 10.1073/pnas.0703113104. View

Snarr B, Wirrig E, Phelps A, Trusk T, Wessels A . A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development. Dev Dyn. 2007; 236(5):1287-94. PMC: 4003411. DOI: 10.1002/dvdy.21074. View

Selever J, Liu W, Lu M, Behringer R, Martin J . Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol. 2004; 276(2):268-79. DOI: 10.1016/j.ydbio.2004.08.024. View

Webb S, Brown N, Anderson R . Formation of the atrioventricular septal structures in the normal mouse. Circ Res. 1998; 82(6):645-56. DOI: 10.1161/01.res.82.6.645. View

Goldman D, Hackenmiller R, Nakayama T, Sopory S, Wong C, Kulessa H . Mutation of an upstream cleavage site in the BMP4 prodomain leads to tissue-specific loss of activity. Development. 2006; 133(10):1933-42. DOI: 10.1242/dev.02368. View

10.

Ma L, Lu M, Schwartz R, Martin J . Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development. 2005; 132(24):5601-11. DOI: 10.1242/dev.02156. View

11.

Zhang H, Bradley A . Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development. 1996; 122(10):2977-86. DOI: 10.1242/dev.122.10.2977. View

12.

Bajolle F, Zaffran S, Kelly R, Hadchouel J, Bonnet D, Brown N . Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries. Circ Res. 2006; 98(3):421-8. DOI: 10.1161/01.RES.0000202800.85341.6e. View

13.

Furuta Y, Hogan B . BMP4 is essential for lens induction in the mouse embryo. Genes Dev. 1998; 12(23):3764-75. PMC: 317259. DOI: 10.1101/gad.12.23.3764. View

14.

Gaussin V, Morley G, Cox L, Zwijsen A, Vance K, Emile L . Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus. Circ Res. 2005; 97(3):219-26. PMC: 2950023. DOI: 10.1161/01.RES.0000177862.85474.63. View

15.

Bandyopadhyay A, Tsuji K, Cox K, Harfe B, Rosen V, Tabin C . Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. 2006; 2(12):e216. PMC: 1713256. DOI: 10.1371/journal.pgen.0020216. View

16.

Gaussin V, van de Putte T, Mishina Y, Hanks M, Zwijsen A, Huylebroeck D . Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci U S A. 2002; 99(5):2878-83. PMC: 122441. DOI: 10.1073/pnas.042390499. View

17.

Liu W, Selever J, Wang D, Lu M, Moses K, Schwartz R . Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodeling. Proc Natl Acad Sci U S A. 2004; 101(13):4489-94. PMC: 384774. DOI: 10.1073/pnas.0308466101. View

18.

Yelbuz T, Waldo K, Kumiski D, Stadt H, Wolfe R, Leatherbury L . Shortened outflow tract leads to altered cardiac looping after neural crest ablation. Circulation. 2002; 106(4):504-10. DOI: 10.1161/01.cir.0000023044.44974.8a. View

19.

Delot E . Control of endocardial cushion and cardiac valve maturation by BMP signaling pathways. Mol Genet Metab. 2003; 80(1-2):27-35. DOI: 10.1016/j.ymgme.2003.07.004. View

20.

Lamers W, Moorman A . Cardiac septation: a late contribution of the embryonic primary myocardium to heart morphogenesis. Circ Res. 2002; 91(2):93-103. DOI: 10.1161/01.res.0000027135.63141.89. View