Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis

Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 1211 BRBII/III, 421 Curie Boulevard., Philadelphia, PA 19104-6058, USA.
Nature Cell Biology (Impact Factor: 19.68). 05/2009; 11(5):637-43. DOI: 10.1038/ncb1870
Source: PubMed


Patterning the embryonic dorsoventral axis of both vertebrates and invertebrates requires signalling through bone morphogenetic proteins (BMPs). Although a well-studied process, the identity of the physiologically relevant BMP signalling complex in the Drosophila melanogaster embryo is controversial, is generally inferred from cell culture studies and has not been investigated in vertebrates. Here, we demonstrate that dorsoventral patterning in zebrafish, Danio rerio, requires two classes of non-redundant type I BMP receptors, Alk3/6 and Alk8 (activin-like kinases 3/6 and 8). We show, under physiological conditions in the embryo, that these two type I receptor classes form a complex in a manner that depends on Bmp2 and Bmp7. We found that both Bmp2-7 heterodimers, as well as Bmp2 and Bmp7 homodimers, form in the embryo. However, only recombinant ligand heterodimers can activate BMP signalling in the early embryo, whereas a combination of Bmp2 and Bmp7 homodimers cannot. We propose that only heterodimers, signalling through two distinct classes of type I receptor, possess sufficient receptor affinity in an environment of extracellular antagonists to elicit the signalling response required for dorsoventral patterning.

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Available from: Shawn C Little, Oct 08, 2015
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    • "Except for them, all the other BMP family members are capable of forming either homodimers or heterodimers. The heterodimers of BMP-2/5, BMP-2/6, BMP-2/7 and BMP-4/7 have been found both in vitro and in vivo and they are all the activated factors playing more effective roles in signal pathway than their corresponding homodimers do [8] [9]. "
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    ABSTRACT: Bone morphogenetic proteins (BMPs) are a family of potent, multifunctional growth factors belonging to transforming growth factor-β (TGF-β). They are highly conservative in structures. Over 20 members of BMPs with varying functions such as embryogenesis, skeletal formation, hematopoesis and neurogenesis have been identified in human body. BMPs are unique growth factors that can induce the formation of bone tissue individually. BMPs can induce the differentiation of bone marrow mesenchymal stem cells into osteoblastic lineage and promote the proliferation of osteoblasts and chondrocytes. BMPs stimulate the target cells by specific membrane-bound receptors and signal transduced through mothers against decapentaplegic (Smads) and mitogen activated protein kinase (MAPKs) pathways. It has been demonstrated that BMP-2, BMP-4, BMP-6, BMP-7, and BMP-9 play an important role in bone formation. This article focuses on the molecular characterization of BMPs family members, mechanism of osteogenesis promotion, related signal pathways of osteogenic function, relationships between structure and osteogenetic activity, and the interactions among family members at bone formation.
    01/2015; 150(3-4). DOI:10.1016/j.fshw.2014.12.002
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    • "It may also be restricted to a very specific region and time. There is evidence in other models for heteromeric receptor formation (Little and Mullins, 2009; Shimmi et al., 2005), but other mechanisms, such as interaction with as yet unidentified regulatory factors, may be responsible. "
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    ABSTRACT: BMP signaling plays an essential role in second heart field-derived heart and arterial trunk development, including myocardial differentiation, right ventricular growth, and interventricular, outflow tract and aortico-pulmonary septation. It is mediated by a number of different BMP ligands, and receptors, many of which are present simultaneously. The mechanisms by which they regulate morphogenetic events and degree of redundancy amongst them have still to be elucidated. We therefore assessed the role of BMP Type I receptor AcvR1 in anterior second heart field-derived cell development, and compared it with that of BmpR1a. By removing Acvr1 using the driver Mef2c[AHF]-Cre, we show that AcvR1 plays an essential role in arterial pole morphogenesis, identifying defects in outflow tract wall and cushion morphology that preceded a spectrum of septation defects from double outlet right ventricle to common arterial trunk in mutants. Its absence caused dysregulation in gene expression important for myocardial differentiation (Isl1, Fgf8) and regional identity (Tbx2, Tbx3, Tbx20, Tgfb2). Although these defects resemble to some degree those in the equivalent Bmpr1a mutant, a novel gene knock-in model in which Bmpr1a was expressed in the Acvr1 locus only partially restored septation in Acvr1 mutants. These data show that both BmpR1a and AcvR1 are needed for normal heart development, in which they play some non-redundant roles, and refine our understanding of the genetic and morphogenetic processes underlying Bmp-mediated heart development important in human congenital heart disease.
    Developmental Biology 06/2014; 390(2). DOI:10.1016/j.ydbio.2014.03.008 · 3.55 Impact Factor
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    • "To delineate the contribution of each BMP type I receptor in the formation of lymphatic vessel, we attenuated the level of Alk1, Alk2, Alk3, and Alk3b activities in zebrafish. Consistent with a previous report (Little and Mullins, 2009), the injections of "
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    ABSTRACT: Lymphatic vessels are essential to regulate interstitial fluid homeostasis and diverse immune responses. A number of crucial factors, such as VEGFC, SOX18, PROX1, FOX2C, and GJC2, have been implicated in differentiation and/or maintenance of lymphatic endothelial cells (LECs). In humans, dysregulation of these genes is known to cause lymphedema, a debilitating condition which adversely impacts the quality of life of affected individuals. However, there are no currently available pharmacological treatments for lymphedema, necessitating identification of additional factors modulating lymphatic development and function which can be targeted for therapy. In this report, we investigate the function of genes associated with Bone Morphogenetic Protein (BMP) signaling in lymphatic development using zebrafish embryos. The knock-down of BMP type II receptors, Bmpr2a and Bmpr2b, and type I receptors, Alk3 and Alk3b, as well as SMAD5, an essential cellular mediator of BMP signaling, led to distinct lymphatic defects in developing zebrafish. Therefore, it appears that each constituent of the BMP signaling pathway may have a unique function during lymphatic development. Taken together, our data demonstrate that BMP signaling is essential for normal lymphatic vessel development in zebrafish.
    Moleculer Cells 03/2014; 37(3). DOI:10.14348/molcells.2014.0005 · 2.09 Impact Factor
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