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Mol Cell Biol
1999 Oct 01;1910:7096-105. doi: 10.1128/MCB.19.10.7096.
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Bone morphogenetic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4.
Monzen K, Shiojima I, Hiroi Y, Kudoh S, Oka T, Takimoto E, Hayashi D, Hosoda T, Habara-Ohkubo A, Nakaoka T, Fujita T, Yazaki Y, Komuro I.
???displayArticle.abstract??? Bone morphogenetic proteins (BMPs) have been shown to induce ectopic expression of cardiac transcription factors and beating cardiomyocytes in nonprecardiac mesodermal cells in chicks, suggesting that BMPs are inductive signaling molecules that participate in the development of the heart. However, the precise molecular mechanisms by which BMPs regulate cardiac development are largely unknown. In the present study, we examined the molecular mechanisms by which BMPs induce cardiac differentiation by using the P19CL6 in vitro cardiomyocyte differentiation system, a clonal derivative of P19 embryonic teratocarcinoma cells. We established a permanent P19CL6 cell line, P19CL6noggin, which constitutively overexpresses the BMP antagonist noggin. Although almost all parental P19CL6 cells differentiate into beating cardiomyocytes when treated with 1% dimethyl sulfoxide, P19CL6noggin cells did not differentiate into beating cardiomyocytes nor did they express cardiac transcription factors or contractile protein genes. The failure of differentiation was rescued by overexpression of BMP-2 or addition of BMP protein to the culture media, indicating that BMPs were indispensable for cardiomyocyte differentiation in this system. Overexpression of TAK1, a member of the mitogen-activated protein kinase kinase kinase superfamily which transduces BMP signaling, restored the ability of P19CL6noggin cells to differentiate into cardiomyocytes and concomitantly express cardiac genes, whereas overexpression of the dominant negative form of TAK1 in parental P19CL6 cells inhibited cardiomyocyte differentiation. Overexpression of both cardiac transcription factors Csx/Nkx-2.5 and GATA-4 but not of Csx/Nkx-2.5 or GATA-4 alone also induced differentiation of P19CL6noggin cells into cardiomyocytes. These results suggest that TAK1, Csx/Nkx-2.5, and GATA-4 play a pivotal role in the cardiogenic BMP signaling pathway.
Andrée,
BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos.
1998, Pubmed
Andrée,
BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos.
1998,
Pubmed Arceci,
Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart.
1993,
Pubmed Bader,
Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro.
1982,
Pubmed Bodmer,
The gene tinman is required for specification of the heart and visceral muscles in Drosophila.
1993,
Pubmed Bodmer,
A new homeobox-containing gene, msh-2, is transiently expressed early during mesoderm formation of Drosophila.
1990,
Pubmed Bour,
Drosophila MEF2, a transcription factor that is essential for myogenesis.
1995,
Pubmed Cleaver,
Overexpression of the tinman-related genes XNkx-2.5 and XNkx-2.3 in Xenopus embryos results in myocardial hyperplasia.
1996,
Pubmed
,
Xenbase Edwards,
Induced muscle differentiation in an embryonal carcinoma cell line.
1983,
Pubmed Evans,
Regulation of Cardiac Gene Expression by GATA-4/5/6.
1997,
Pubmed Frasch,
Induction of visceral and cardiac mesoderm by ectodermal Dpp in the early Drosophila embryo.
1995,
Pubmed Fu,
Cardiac myogenesis: overexpression of XCsx2 or XMEF2A in whole Xenopus embryos induces the precocious expression of XMHCα gene.
1995,
Pubmed
,
Xenbase Gajewski,
D-mef2 is a target for Tinman activation during Drosophila heart development.
1997,
Pubmed Gonzalez-Sanchez,
In vitro analysis of cardiac progenitor cell differentiation.
1990,
Pubmed Graff,
Studies with a Xenopus BMP receptor suggest that ventral mesoderm-inducing signals override dorsal signals in vivo.
1994,
Pubmed
,
Xenbase Grépin,
A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription.
1994,
Pubmed
,
Xenbase Grépin,
Enhanced cardiogenesis in embryonic stem cells overexpressing the GATA-4 transcription factor.
1997,
Pubmed Habara-Ohkubo,
Differentiation of beating cardiac muscle cells from a derivative of P19 embryonal carcinoma cells.
1996,
Pubmed Han,
Expression of sarcomeric myosin in the presumptive myocardium of chicken embryos occurs within six hours of myocyte commitment.
1992,
Pubmed Hawley,
Disruption of BMP signals in embryonic Xenopus ectoderm leads to direct neural induction.
1995,
Pubmed
,
Xenbase Heldin,
TGF-beta signalling from cell membrane to nucleus through SMAD proteins.
1997,
Pubmed Holtzer,
Autonomous expression of the differentiation programs of cells in the cardiac and skeletal myogenic lineages.
1990,
Pubmed Ip,
The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells.
1994,
Pubmed Jacobson,
Features of embryonic induction.
1988,
Pubmed Johansson,
Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development.
1995,
Pubmed
,
Xenbase Komuro,
Csx: a murine homeobox-containing gene specifically expressed in the developing heart.
1993,
Pubmed Kuo,
GATA4 transcription factor is required for ventral morphogenesis and heart tube formation.
1997,
Pubmed Lee,
Twist-mediated activation of the NK-4 homeobox gene in the visceral mesoderm of Drosophila requires two distinct clusters of E-box regulatory elements.
1997,
Pubmed Lee,
The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression.
1998,
Pubmed Lilly,
Requirement of MADS domain transcription factor D-MEF2 for muscle formation in Drosophila.
1995,
Pubmed Lin,
Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C.
1997,
Pubmed Lints,
Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants.
1993,
Pubmed Lyons,
Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.
1995,
Pubmed Maéno,
A truncated bone morphogenetic protein 4 receptor alters the fate of ventral mesoderm to dorsal mesoderm: roles of animal pole tissue in the development of ventral mesoderm.
1994,
Pubmed
,
Xenbase Martin,
Teratocarcinomas and mammalian embryogenesis.
1980,
Pubmed McBurney,
Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line.
1982,
Pubmed McMahon,
Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite.
1998,
Pubmed Minden,
Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK.
1994,
Pubmed Molkentin,
Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene.
1994,
Pubmed Molkentin,
Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis.
1997,
Pubmed Moriguchi,
A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3.
1996,
Pubmed Nakaoka,
Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2.
1997,
Pubmed Nascone,
An inductive role for the endoderm in Xenopus cardiogenesis.
1995,
Pubmed
,
Xenbase Olson,
Molecular pathways controlling heart development.
1996,
Pubmed Ranganayakulu,
A series of mutations in the D-MEF2 transcription factor reveal multiple functions in larval and adult myogenesis in Drosophila.
1995,
Pubmed Reshef,
Regulation of dorsal somitic cell fates: BMPs and Noggin control the timing and pattern of myogenic regulator expression.
1998,
Pubmed Sater,
The restriction of the heart morphogenetic field in Xenopus laevis.
1990,
Pubmed
,
Xenbase Schultheiss,
A role for bone morphogenetic proteins in the induction of cardiac myogenesis.
1997,
Pubmed Schultheiss,
Induction of avian cardiac myogenesis by anterior endoderm.
1995,
Pubmed
,
Xenbase Sepulveda,
GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression.
1998,
Pubmed
,
Xenbase Serbedzija,
Regulation in the heart field of zebrafish.
1998,
Pubmed
,
Xenbase Shibuya,
Role of TAK1 and TAB1 in BMP signaling in early Xenopus development.
1998,
Pubmed
,
Xenbase Shiojima,
Context-dependent transcriptional cooperation mediated by cardiac transcription factors Csx/Nkx-2.5 and GATA-4.
1999,
Pubmed Shiojima,
Molecular cloning and characterization of human cardiac homeobox gene CSX1.
1996,
Pubmed Simon,
Gotta have GATA.
1995,
Pubmed Skerjanc,
Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other's expression and initiate cardiomyogenesis in P19 cells.
1998,
Pubmed
,
Xenbase Smith,
Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos.
1992,
Pubmed
,
Xenbase Steinbeisser,
The role of gsc and BMP-4 in dorsal-ventral patterning of the marginal zone in Xenopus: a loss-of-function study using antisense RNA.
1995,
Pubmed
,
Xenbase Sugi,
Activin-A and FGF-2 mimic the inductive effects of anterior endoderm on terminal cardiac myogenesis in vitro.
1995,
Pubmed Suzuki,
A truncated bone morphogenetic protein receptor affects dorsal-ventral patterning in the early Xenopus embryo.
1994,
Pubmed
,
Xenbase Takano,
The Rho family G proteins play a critical role in muscle differentiation.
1998,
Pubmed Winnier,
Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.
1995,
Pubmed Xu,
Smad proteins act in combination with synergistic and antagonistic regulators to target Dpp responses to the Drosophila mesoderm.
1998,
Pubmed Yamaguchi,
Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction.
1995,
Pubmed Zhang,
Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development.
1996,
Pubmed Zimmerman,
The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.
1996,
Pubmed
,
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