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Eric N Olson - One of the best experts on this subject based on the ideXlab platform.
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neuronal myocyte specific enhancer factor 2d mef2d is required for normal circadian and sleep behavior in mice
The Journal of Neuroscience, 2019Co-Authors: Jennifer A Mohawk, Makito Sato, Masashi Yanagisawa, Eric N Olson, Joseph S. TakahashiAbstract:The transcription factor, myocyte enhancer factor-2 (MEF2), is required for normal circadian behavior in Drosophila; however, its role in the mammalian circadian system has not been established. Of the four mammalian Mef2 genes, Mef2d is highly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, a region critical for coordinating peripheral circadian clocks. Utilizing both conventional and brain-specific Mef2d knockout (Mef2d-/-) mouse lines, we demonstrate that MEF2D is essential for maintaining the length of the circadian free-running period of locomotor activity and normal sleep patterns in male mice. Crossing Mef2d-/- with Per2::luc reporter mice, we show that these behavioral changes are achieved without altering the endogenous period of the master circadian oscillator in the SCN. Together, our data suggest that alterations in behavior in Mef2d-/- mice may be the result of an effect on SCN output, rather than an effect on timekeeping within the SCN itself. These findings add to the growing body of evidence that MEF2 proteins play important roles in the brain. SIGNIFICANCE STATEMENT These studies are the first to show a role for MEF2 proteins in the brain outside of the hippocampus, and our findings suggest that these proteins may play diverse roles in the central nervous system. It is important to continue to build on our understanding of the roles of proteins acting in the SCN, because SCN dysfunction underlies jet lag in humans and influences the response to shift work schedules, which are now known as risk factors for the development of cancer. Our work on MEF2D could be the basis for opening new lines of research in the development and regulation of circadian rhythms.
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the mef2d transcription factor mediates stress dependent cardiac remodeling in mice
Journal of Clinical Investigation, 2008Co-Authors: Dillon Phan, Eva Van Rooij, Joseph A. Hill, Xiaoxia Qi, John Mcanally, James A Richardson, Rhonda S Basselduby, Eric N OlsonAbstract:The adult heart responds to excessive neurohumoral signaling and workload by a pathological growth response characterized by hypertrophy of cardiomyocytes and activation of a fetal program of cardiac gene expression. These responses culminate in diminished pump function, ventricular dilatation, wall thinning, and fibrosis, and can result in sudden death. Myocyte enhancer factor–2 (MEF2) transcription factors serve as targets of the signaling pathways that drive pathological cardiac remodeling, but the requirement for MEF2 factors in the progression of heart disease in vivo has not been determined. MEF2A and MEF2D are the primary MEF2 factors expressed in the adult heart. To specifically determine the role of MEF2D in pathological cardiac remodeling, we generated mice with a conditional MEF2D allele. MEF2D-null mice were viable, but were resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and β-chronic adrenergic stimulation. Furthermore, we show in a transgenic mouse model that forced overexpression of MEF2D was sufficient to drive the fetal gene program and pathological remodeling of the heart. These results reveal a unique and important function for MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart.
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Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by MEF2C.
Molecular and cellular biology, 2007Co-Authors: Matthew J. Potthoff, John Mcanally, James A Richardson, Michael A Arnold, Rhonda S Bassel-duby, Eric N OlsonAbstract:Myocyte enhancer factor 2 (MEF2) transcription factors cooperate with the MyoD family of basic helix-loop-helix (bHLH) transcription factors to drive skeletal muscle development during embryogenesis, but little is known about the potential functions of MEF2 factors in postnatal skeletal muscle. Here we show that skeletal muscle-specific deletion of MEF2C in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d is required for normal skeletal muscle development in vivo. Skeletal muscle deficient in MEF2C differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M line. Microarray analysis of MEF2C null muscles identified several muscle structural genes that depend on MEF2C, including those encoding the M-line-specific proteins myomesin and M protein. We show that MEF2C directly regulates myomesin gene transcription and that loss of MEF2C in skeletal muscle results in improper sarcomere organization. These results reveal a key role for MEF2C in maintenance of sarcomere integrity and postnatal maturation of skeletal muscle.
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MEF2C transcription factor controls chondrocyte hypertrophy and bone development
Developmental Cell, 2007Co-Authors: Michael A Arnold, Dillon Phan, John Mcanally, James A Richardson, Rhonda S Basselduby, Yuri Kim, Michael P Czubryt, John M Shelton, Eric N OlsonAbstract:Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of MEF2C or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of MEF2C mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous MEF2C mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.
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bop a regulator of right ventricular heart development is a direct transcriptional target of MEF2C in the developing heart
Development, 2005Co-Authors: Dillon Phan, John Mcanally, James A Richardson, Rhonda S Basselduby, Tara L Rasmussen, Osamu Nakagawa, Paul D Gottlieb, Philip W Tucker, Eric N OlsonAbstract:The vertebrate heart is assembled during embryogenesis in a modular manner from different populations of precursor cells. The right ventricular chamber and outflow tract are derived primarily from a population of progenitors known as the anterior heart field. These regions of the heart are severely hypoplastic in mutant mice lacking the myocyte enhancer factor 2C (MEF2C) and BOP transcription factors, suggesting that these cardiogenic regulatory factors may act in a common pathway for development of the anterior heart field and its derivatives. We show that Bop expression in the developing heart depends on the direct binding of MEF2C to a MEF2-response element in the Bop promoter that is necessary and sufficient to recapitulate endogenous Bop expression in the anterior heart field and its cardiac derivatives during mouse development. The Bop promoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF2. These findings identify Bop as an essential downstream effector gene of MEF2C in the developing heart, and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives.
Brian L Black - One of the best experts on this subject based on the ideXlab platform.
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Cardiovascular development and survival require MEF2C function in the myocardial but not the endothelial lineage.
Developmental biology, 2018Co-Authors: Stefan C. Materna, Tanvi Sinha, Ralston M. Barnes, Kelly Lammerts Van Bueren, Brian L BlackAbstract:MEF2C is a member of the highly conserved MEF2 family of transcription factors and is a key regulator of cardiovascular development. In mice, MEF2C is expressed in the developing heart and vasculature, including the endothelium. Loss of MEF2C function in germline knockout mice leads to early embryonic demise and profound developmental abnormalities in the cardiovascular system. Previous attempts to uncover the cause of embryonic lethality by specifically disrupting MEF2C function in the heart or vasculature failed to recapitulate the global MEF2C knockout phenotype and instead resulted in relatively minor defects that did not compromise viability or result in significant cardiovascular defects. However, previous studies examined the requirement of MEF2C in the myocardial and endothelial lineages using Cre lines that begin to be expressed after the expression of MEF2C has already commenced. Here, we tested the requirement of MEF2C in the myocardial and endothelial lineages using conditional knockout approaches in mice with Cre lines that deleted MEF2C prior to onset of its expression in embryonic development. We found that deletion of MEF2C in the early myocardial lineage using Nkx2-5Cre resulted in cardiac and vascular abnormalities that were indistinguishable from the defects in the global MEF2C knockout. In contrast, early deletion of MEF2C in the vascular endothelium using an Etv2::Cre line active prior to the onset of MEF2C expression resulted in viable offspring that were indistinguishable from wild type controls with no overt defects in vascular development, despite nearly complete early deletion of MEF2C in the vascular endothelium. Thus, these studies support the idea that the requirement of MEF2C for vascular development is secondary to its requirement in the heart and suggest that the observed failure in vascular remodeling in MEF2C knockout mice results from defective heart function.
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The Transcription Factor MEF2C Is Required for Craniofacial Development
Developmental cell, 2007Co-Authors: Michael P. Verzi, John J Schwarz, Pooja Agarwal, David J. Mcculley, Courtney Brown, Brian L BlackAbstract:MEF2 transcription factors are well-established regulators of muscle development. We have discovered an unanticipated role for MEF2C in the neural crest, where tissue-specific inactivation results in neonatal lethality due to severe craniofacial defects. We show that MEF2C is required for expression of the Dlx5, Dlx6, and Hand2 transcription factor genes in the branchial arches, and we identify a branchial arch-specific enhancer in the Dlx5/6 locus, which is activated synergistically by MEF2C and Dlx5, demonstrating that these factors interact to induce transcription. MEF2C and Dlx5/6 also interact genetically. Mice heterozygous for either Dlx5/6 or MEF2C are normal at birth and survive to weaning. By contrast, heterozygosity for both MEF2C and Dlx5/6 results in defective palate development and neonatal lethality. Taken together, the studies presented here define a feed-forward transcriptional circuit between the MADS-box transcription factor MEF2C and the homeodomain transcription factors Dlx5 and Dlx6 in craniofacial development.
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MEF2C is activated directly by Ets transcription factors through an evolutionarily conserved endothelial cell-specific enhancer.
Developmental biology, 2004Co-Authors: Sarah De Val, Analeah B Heidt, Joshua P. Anderson, Dustin Khiem, Brian L BlackAbstract:Members of the Myocyte Enhancer Factor 2 (MEF2) family of transcription factors play key roles in the development and differentiation of numerous cell types during mammalian development, including the vascular endothelium. MEF2C is expressed very early in the development of the endothelium, and genetic studies in mice have demonstrated that MEF2C is required for vascular development. However, the transcriptional pathways involving MEF2C during endothelial cell development have not been defined. As a first step towards identifying the transcriptional factors upstream of MEF2C in the vascular endothelium, we screened for transcriptional enhancers from the mouse MEF2C gene that regulate vascular expression in vivo. In this study, we identified a transcriptional enhancer from the mouse MEF2C gene sufficient to direct expression to the vascular endothelium in transgenic embryos. This enhancer is active in endothelial cells within the developing vascular system from very early stages in vasculogenesis, and the enhancer remains robustly active in the vascular endothelium during embryogenesis and in adulthood. This MEF2C endothelial cell enhancer contains four perfect consensus Ets transcription factor binding sites that are efficiently bound by Ets-1 protein in vitro and are required for enhancer function in transgenic embryos. Thus, these studies identify MEF2C as a direct transcriptional target of Ets factors via an evolutionarily conserved transcriptional enhancer and establish a direct link between these two early regulators of vascular gene expression during endothelial cell development in vivo.
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MEF2C is activated directly by myogenic basic helix loop helix proteins during skeletal muscle development in vivo
Mechanisms of Development, 2003Co-Authors: Evdokia Dodou, Brian L BlackAbstract:Skeletal muscle development requires the coordinated expression of numerous transcription factors to control the specification of mesodermal progenitor cells to a muscle fate and the differentiation of those committed myoblasts into functional, contractile muscle. Two families of transcription factors play key roles in these processes. The myogenic basic helix-loop-helix (bHLH) proteins, MyoD and Myf5, are required for myoblast specification, while two members of the same family, myogenin and MRF4, play key roles in myoblast differentiation in vivo. All four members of the myogenic bHLH family are sufficient to dominantly induce myogenesis when introduced into a variety of non-muscle cells in culture, however this function requires the activity of a second family of transcriptional regulators, the myocyte enhancer factor 2 (MEF2) family. MEF2 factors are essential for muscle differentiation, and previous studies have shown that MyoD and MEF2 family members function combinatorially to activate transcription and myogenesis. Consistent with these observations, the majority of skeletal muscle genes require both MyoD and MEF2 family members to activate their transcription. A possible exception to this combinatorial model for activation is suggested by the observation that myogenic bHLH factors may be able to independently activate the expression of MEF2. This raises the question as to how mef2 gene transcription is induced by MyoD factors without cooperative activation by MEF2. During skeletal muscle development, MEF2C is the first member of the MEF2 family to be expressed. In this study, we have investigated the regulation of a skeletal muscle-specific enhancer from the mouse MEF2C gene using a transgenic approach. We show that MEF2C is a direct transcriptional target of the MyoD family in vivo via an essential E box in the skeletal muscle enhancer of MEF2C, and we show that MEF2C is not a direct target for autoregulation by MEF2.
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mutational analysis of the dna binding dimerization and transcriptional activation domains of MEF2C
Molecular and Cellular Biology, 1996Co-Authors: Jeffery D Molkentin, James F Martin, Brian L Black, Eric N OlsonAbstract:There are four members of the myocyte enhancer factor 2 (MEF2) family of transcription factors in vertebrates, MEF2A, -B, -C, and -D, which have homology within a MADS box at their amino termini and an adjacent motif known as the MEF2 domain. These factors activate muscle gene expression by binding as homo- and heterodimers to an A/T-rich DNA sequence in the control regions of muscle-specific genes. To understand the mechanisms of muscle gene activation of MEF2 factors, we generated a series of deletion and site-directed mutants of MEF2C. These mutants demonstrated that the MADS and MEF2 domains mediate DNA binding and dimerization, whereas the carboxyl terminus is required for transcriptional activation. Amino acids that are essential for MEF2 site-dependent transcription but which do not affect DNA binding were also identified in the MEF2 domain. This type of positive-control mutant demonstrates that the transcription activation domain of MEF2C, although separate from the MEF2 domain, is dependent on this domain for transcriptional activation through the MEF2 site. MEF2 mutants that are defective for DNA binding act as dominant negative mutants and can inhibit activation of MEF2-dependent genes by wild-type MEF2C.
James A Richardson - One of the best experts on this subject based on the ideXlab platform.
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the mef2d transcription factor mediates stress dependent cardiac remodeling in mice
Journal of Clinical Investigation, 2008Co-Authors: Dillon Phan, Eva Van Rooij, Joseph A. Hill, Xiaoxia Qi, John Mcanally, James A Richardson, Rhonda S Basselduby, Eric N OlsonAbstract:The adult heart responds to excessive neurohumoral signaling and workload by a pathological growth response characterized by hypertrophy of cardiomyocytes and activation of a fetal program of cardiac gene expression. These responses culminate in diminished pump function, ventricular dilatation, wall thinning, and fibrosis, and can result in sudden death. Myocyte enhancer factor–2 (MEF2) transcription factors serve as targets of the signaling pathways that drive pathological cardiac remodeling, but the requirement for MEF2 factors in the progression of heart disease in vivo has not been determined. MEF2A and MEF2D are the primary MEF2 factors expressed in the adult heart. To specifically determine the role of MEF2D in pathological cardiac remodeling, we generated mice with a conditional MEF2D allele. MEF2D-null mice were viable, but were resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and β-chronic adrenergic stimulation. Furthermore, we show in a transgenic mouse model that forced overexpression of MEF2D was sufficient to drive the fetal gene program and pathological remodeling of the heart. These results reveal a unique and important function for MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart.
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Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by MEF2C.
Molecular and cellular biology, 2007Co-Authors: Matthew J. Potthoff, John Mcanally, James A Richardson, Michael A Arnold, Rhonda S Bassel-duby, Eric N OlsonAbstract:Myocyte enhancer factor 2 (MEF2) transcription factors cooperate with the MyoD family of basic helix-loop-helix (bHLH) transcription factors to drive skeletal muscle development during embryogenesis, but little is known about the potential functions of MEF2 factors in postnatal skeletal muscle. Here we show that skeletal muscle-specific deletion of MEF2C in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d is required for normal skeletal muscle development in vivo. Skeletal muscle deficient in MEF2C differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M line. Microarray analysis of MEF2C null muscles identified several muscle structural genes that depend on MEF2C, including those encoding the M-line-specific proteins myomesin and M protein. We show that MEF2C directly regulates myomesin gene transcription and that loss of MEF2C in skeletal muscle results in improper sarcomere organization. These results reveal a key role for MEF2C in maintenance of sarcomere integrity and postnatal maturation of skeletal muscle.
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MEF2C transcription factor controls chondrocyte hypertrophy and bone development
Developmental Cell, 2007Co-Authors: Michael A Arnold, Dillon Phan, John Mcanally, James A Richardson, Rhonda S Basselduby, Yuri Kim, Michael P Czubryt, John M Shelton, Eric N OlsonAbstract:Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of MEF2C or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of MEF2C mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous MEF2C mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.
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bop a regulator of right ventricular heart development is a direct transcriptional target of MEF2C in the developing heart
Development, 2005Co-Authors: Dillon Phan, John Mcanally, James A Richardson, Rhonda S Basselduby, Tara L Rasmussen, Osamu Nakagawa, Paul D Gottlieb, Philip W Tucker, Eric N OlsonAbstract:The vertebrate heart is assembled during embryogenesis in a modular manner from different populations of precursor cells. The right ventricular chamber and outflow tract are derived primarily from a population of progenitors known as the anterior heart field. These regions of the heart are severely hypoplastic in mutant mice lacking the myocyte enhancer factor 2C (MEF2C) and BOP transcription factors, suggesting that these cardiogenic regulatory factors may act in a common pathway for development of the anterior heart field and its derivatives. We show that Bop expression in the developing heart depends on the direct binding of MEF2C to a MEF2-response element in the Bop promoter that is necessary and sufficient to recapitulate endogenous Bop expression in the anterior heart field and its cardiac derivatives during mouse development. The Bop promoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF2. These findings identify Bop as an essential downstream effector gene of MEF2C in the developing heart, and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives.
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the MEF2C gene is a direct transcriptional target of myogenic bhlh and mef2 proteins during skeletal muscle development
Development, 2001Co-Authors: Dazhi Wang, John Mcanally, James A Richardson, Renee M Valdez, Eric N OlsonAbstract:Members of the MEF2 family of transcription factors are upregulated during skeletal muscle differentiation and cooperate with the MyoD family of myogenic basic helix-loop-helix (bHLH) transcription factors to control the expression of muscle-specific genes. To determine the mechanisms that regulate MEF2 gene expression during skeletal muscle development, we analyzed the mouse MEF2C gene for cis-regulatory elements that direct expression in the skeletal muscle lineage in vivo. We describe a skeletal muscle-specific control region for MEF2C that is sufficient to direct lacZ reporter gene expression in a pattern that recapitulates that of the endogenous MEF2C gene in skeletal muscle during pre- and postnatal development. This control region is a direct target for the binding of myogenic bHLH and MEF2 proteins. Mutagenesis of the MEF2C control region shows that a binding site for myogenic bHLH proteins is essential for expression at all stages of skeletal muscle development, whereas an adjacent MEF2 binding site is required for maintenance but not for initiation of MEF2C transcription. Our findings reveal the existence of a regulatory circuit between these two classes of transcription factors that induces, amplifies and maintains their expression during skeletal muscle development.
John Mcanally - One of the best experts on this subject based on the ideXlab platform.
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the mef2d transcription factor mediates stress dependent cardiac remodeling in mice
Journal of Clinical Investigation, 2008Co-Authors: Dillon Phan, Eva Van Rooij, Joseph A. Hill, Xiaoxia Qi, John Mcanally, James A Richardson, Rhonda S Basselduby, Eric N OlsonAbstract:The adult heart responds to excessive neurohumoral signaling and workload by a pathological growth response characterized by hypertrophy of cardiomyocytes and activation of a fetal program of cardiac gene expression. These responses culminate in diminished pump function, ventricular dilatation, wall thinning, and fibrosis, and can result in sudden death. Myocyte enhancer factor–2 (MEF2) transcription factors serve as targets of the signaling pathways that drive pathological cardiac remodeling, but the requirement for MEF2 factors in the progression of heart disease in vivo has not been determined. MEF2A and MEF2D are the primary MEF2 factors expressed in the adult heart. To specifically determine the role of MEF2D in pathological cardiac remodeling, we generated mice with a conditional MEF2D allele. MEF2D-null mice were viable, but were resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and β-chronic adrenergic stimulation. Furthermore, we show in a transgenic mouse model that forced overexpression of MEF2D was sufficient to drive the fetal gene program and pathological remodeling of the heart. These results reveal a unique and important function for MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart.
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Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by MEF2C.
Molecular and cellular biology, 2007Co-Authors: Matthew J. Potthoff, John Mcanally, James A Richardson, Michael A Arnold, Rhonda S Bassel-duby, Eric N OlsonAbstract:Myocyte enhancer factor 2 (MEF2) transcription factors cooperate with the MyoD family of basic helix-loop-helix (bHLH) transcription factors to drive skeletal muscle development during embryogenesis, but little is known about the potential functions of MEF2 factors in postnatal skeletal muscle. Here we show that skeletal muscle-specific deletion of MEF2C in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d is required for normal skeletal muscle development in vivo. Skeletal muscle deficient in MEF2C differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M line. Microarray analysis of MEF2C null muscles identified several muscle structural genes that depend on MEF2C, including those encoding the M-line-specific proteins myomesin and M protein. We show that MEF2C directly regulates myomesin gene transcription and that loss of MEF2C in skeletal muscle results in improper sarcomere organization. These results reveal a key role for MEF2C in maintenance of sarcomere integrity and postnatal maturation of skeletal muscle.
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MEF2C transcription factor controls chondrocyte hypertrophy and bone development
Developmental Cell, 2007Co-Authors: Michael A Arnold, Dillon Phan, John Mcanally, James A Richardson, Rhonda S Basselduby, Yuri Kim, Michael P Czubryt, John M Shelton, Eric N OlsonAbstract:Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of MEF2C or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of MEF2C mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous MEF2C mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.
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bop a regulator of right ventricular heart development is a direct transcriptional target of MEF2C in the developing heart
Development, 2005Co-Authors: Dillon Phan, John Mcanally, James A Richardson, Rhonda S Basselduby, Tara L Rasmussen, Osamu Nakagawa, Paul D Gottlieb, Philip W Tucker, Eric N OlsonAbstract:The vertebrate heart is assembled during embryogenesis in a modular manner from different populations of precursor cells. The right ventricular chamber and outflow tract are derived primarily from a population of progenitors known as the anterior heart field. These regions of the heart are severely hypoplastic in mutant mice lacking the myocyte enhancer factor 2C (MEF2C) and BOP transcription factors, suggesting that these cardiogenic regulatory factors may act in a common pathway for development of the anterior heart field and its derivatives. We show that Bop expression in the developing heart depends on the direct binding of MEF2C to a MEF2-response element in the Bop promoter that is necessary and sufficient to recapitulate endogenous Bop expression in the anterior heart field and its cardiac derivatives during mouse development. The Bop promoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF2. These findings identify Bop as an essential downstream effector gene of MEF2C in the developing heart, and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives.
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the MEF2C gene is a direct transcriptional target of myogenic bhlh and mef2 proteins during skeletal muscle development
Development, 2001Co-Authors: Dazhi Wang, John Mcanally, James A Richardson, Renee M Valdez, Eric N OlsonAbstract:Members of the MEF2 family of transcription factors are upregulated during skeletal muscle differentiation and cooperate with the MyoD family of myogenic basic helix-loop-helix (bHLH) transcription factors to control the expression of muscle-specific genes. To determine the mechanisms that regulate MEF2 gene expression during skeletal muscle development, we analyzed the mouse MEF2C gene for cis-regulatory elements that direct expression in the skeletal muscle lineage in vivo. We describe a skeletal muscle-specific control region for MEF2C that is sufficient to direct lacZ reporter gene expression in a pattern that recapitulates that of the endogenous MEF2C gene in skeletal muscle during pre- and postnatal development. This control region is a direct target for the binding of myogenic bHLH and MEF2 proteins. Mutagenesis of the MEF2C control region shows that a binding site for myogenic bHLH proteins is essential for expression at all stages of skeletal muscle development, whereas an adjacent MEF2 binding site is required for maintenance but not for initiation of MEF2C transcription. Our findings reveal the existence of a regulatory circuit between these two classes of transcription factors that induces, amplifies and maintains their expression during skeletal muscle development.
Jiingdwan Lee - One of the best experts on this subject based on the ideXlab platform.
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bmk1 erk5 regulates serum induced early gene expression through transcription factor MEF2C
The EMBO Journal, 1997Co-Authors: Yutaka Kato, Vladimir V Kravchenko, Richard I Tapping, Jiahuai Han, Richard J Ulevitch, Jiingdwan LeeAbstract:Big MAP kinase 1 (BMK1), also known as ERK5, is a mitogen-activated protein (MAP) kinase member whose biological role is largely undefined. We have shown previously that the activity of BMK1 in rat smooth muscle cells is up-regulated by oxidants. Here, we describe a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo. Through utilization of MEK5(D), we have determined that a member of the MEF2 transcription factor family, MEF2C, is a protein substrate of BMK1. BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor. Serum is also a potent stimulator of BMK1-induced MEF2C phosphorylation, since a dominant-negative form of BMK1 specifically inhibits serum-induced activation of MEF2C. One consequence of MEF2C activation is increased transcription of the c-jun gene. Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum-induced early gene expression through the transcription factor MEF2C.
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BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C
The EMBO journal, 1997Co-Authors: Yutaka Kato, Vladimir V Kravchenko, Richard I Tapping, Jiahuai Han, Richard J Ulevitch, Jiingdwan LeeAbstract:Big MAP kinase 1 (BMK1), also known as ERK5, is a mitogen-activated protein (MAP) kinase member whose biological role is largely undefined. We have shown previously that the activity of BMK1 in rat smooth muscle cells is up-regulated by oxidants. Here, we describe a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo. Through utilization of MEK5(D), we have determined that a member of the MEF2 transcription factor family, MEF2C, is a protein substrate of BMK1. BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor. Serum is also a potent stimulator of BMK1-induced MEF2C phosphorylation, since a dominant-negative form of BMK1 specifically inhibits serum-induced activation of MEF2C. One consequence of MEF2C activation is increased transcription of the c-jun gene. Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum-induced early gene expression through the transcription factor MEF2C.