The multifaceted role of Notch in cardiac development and disease

Notch receptors and their cognate ligands transduce crucial signals between cells in various tissues, and have been conserved across millions of years of evolution. Mutations in Notch signalling components result in congenital heart defects in humans and mice, demonstrating an essential role for Notch in cardiovascular development. The results of recent experiments implicate this signalling pathway in many stages of heart development, and provide mechanistic insight into the vital functions of Notch in the aetiology of several common forms of paediatric and adult cardiac disease.

[1]  T. Mak,et al.  Disruption of the mouse RBP-J kappa gene results in early embryonic death. , 1995, Development.

[2]  W. Pear,et al.  Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation* , 2005, Journal of Biological Chemistry.

[3]  Linheng Li,et al.  Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation , 2004, Circulation research.

[4]  I. Krantz,et al.  Analysis of Cardiovascular Phenotype and Genotype-Phenotype Correlation in Individuals With a JAG1 Mutation and/or Alagille Syndrome , 2002, Circulation.

[5]  A. Hamosh,et al.  Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. , 2001, Human molecular genetics.

[6]  T. Gridley Notch signaling in vascular development and physiology , 2007, Development.

[7]  S. Tonegawa,et al.  Skeletal and CNS Defects in Presenilin-1-Deficient Mice , 1997, Cell.

[8]  Manfred Gessler,et al.  Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis , 1999, Mechanisms of Development.

[9]  T. Mak,et al.  Disruption of the mouse RBP-Jκ gene results in early embryonic death , 1995 .

[10]  D. Srivastava,et al.  Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Weinmaster,et al.  Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. , 1998, Genes & development.

[12]  E. Ballestar,et al.  Notch signaling is essential for ventricular chamber development. , 2007, Developmental cell.

[13]  MichelaNoseda,et al.  Smooth Muscle α-Actin Is a Direct Target of Notch/CSL , 2006 .

[14]  C. Birchmeier,et al.  Multiple essential functions of neuregulin in development , 1995, Nature.

[15]  G. Weinmaster,et al.  Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. , 1999, Human molecular genetics.

[16]  C. Steidl,et al.  Combined Loss of Hey 1 and HeyL Causes Congenital Heart Defects Because of Impaired Epithelial to Mesenchymal Transition , 2007 .

[17]  R. Johnson,et al.  Identification and expression of a novel family of bHLH cDNAs related to Drosophila hairy and enhancer of split. , 1999, Biochemical and biophysical research communications.

[18]  M. Nieto,et al.  The snail superfamily of zinc-finger transcription factors , 2002, Nature Reviews Molecular Cell Biology.

[19]  A. Fischer,et al.  Phenotypic variability in Hey2 −/− mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome , 2004, Mammalian Genome.

[20]  E. Zackai,et al.  Jagged1 mutations in patients ascertained with isolated congenital heart defects. , 1999, American journal of medical genetics.

[21]  J. Epstein,et al.  RBP-J (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells , 2007, Proceedings of the National Academy of Sciences.

[22]  B. Black,et al.  Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. , 1998, Annual review of cell and developmental biology.

[23]  B. Birren,et al.  The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries , 1998, Nature Genetics.

[24]  C. Steidl,et al.  Combined Loss of Hey1 and HeyL Causes Congenital Heart Defects Because of Impaired Epithelial to Mesenchymal Transition , 2007, Circulation research.

[25]  L. Kedes,et al.  HERP1 Is a Cell Type-specific Primary Target of Notch* , 2002, The Journal of Biological Chemistry.

[26]  J. Epstein,et al.  Cardiac neural crest. , 2005, Seminars in cell & developmental biology.

[27]  D. Srivastava,et al.  Mutations in NOTCH1 cause aortic valve disease , 2005, Nature.

[28]  Y. Jan,et al.  Tetralogy of Fallot and Other Congenital Heart Defects in Hey2 Mutant Mice , 2002, Current Biology.

[29]  M. Iruela-Arispe,et al.  Notch signaling in blood vessels: who is talking to whom about what? , 2007, Circulation research.

[30]  Randy L. Johnson,et al.  Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. , 2005, Developmental biology.

[31]  B. Klonjkowski,et al.  Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. , 2004, Genes & development.

[32]  D. Srivastava,et al.  Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function , 2007, Proceedings of the National Academy of Sciences.

[33]  S. Chiba Notch signaling in stem cell systems. , 2006, Stem cells.

[34]  S. Bray Notch signalling: a simple pathway becomes complex , 2006, Nature Reviews Molecular Cell Biology.

[35]  J. Epstein,et al.  An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. , 2007, The Journal of clinical investigation.

[36]  B. Black,et al.  Activated Notch Inhibits Myogenic Activity of the MADS-Box Transcription Factor Myocyte Enhancer Factor 2C , 1999, Molecular and Cellular Biology.

[37]  Michael Litt,et al.  Mutations of presenilin genes in dilated cardiomyopathy and heart failure. , 2006, American journal of human genetics.

[38]  M. Chin,et al.  Abstract 1238: CHF1/Hey2 Plays a Pivotal Role in Left Ventricular Maturation through Suppression of Ectopic Atrial Gene Expression , 2006 .

[39]  A. Fischer,et al.  Hey Basic Helix-Loop-Helix Transcription Factors Are Repressors of GATA4 and GATA6 and Restrict Expression of the GATA Target Gene ANF in Fetal Hearts , 2005, Molecular and Cellular Biology.

[40]  J. R. Coleman,et al.  Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. , 1999, Development.

[41]  G. Weinmaster,et al.  Notch1 is essential for postimplantation development in mice. , 1994, Genes & development.

[42]  U. Lendahl,et al.  Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation , 2003, Development.

[43]  J. Weissenbach,et al.  Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia , 1996, Nature.

[44]  R. Liao,et al.  Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4. , 2006, American journal of physiology. Heart and circulatory physiology.

[45]  Y. Saga,et al.  Hesr 1 and Hesr 2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx 2 , 2022 .

[46]  B. Gersh,et al.  CALCIFIC AORTIC STENOSIS: FROM BENCH TO THE BEDSIDE—EMERGING CLINICAL AND CELLULAR CONCEPTS , 2003, Heart.

[47]  C. Lien,et al.  Gene Expression Analysis of Zebrafish Heart Regeneration , 2006, PLoS biology.

[48]  David J. Anderson,et al.  Molecular Distinction and Angiogenic Interaction between Embryonic Arteries and Veins Revealed by ephrin-B2 and Its Receptor Eph-B4 , 1998, Cell.

[49]  L. Kedes,et al.  HERP1 Inhibits Myocardin-Induced Vascular Smooth Muscle Cell Differentiation by Interfering With SRF Binding to CArG Box , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[50]  I. Krantz,et al.  Vascular Anomalies in Alagille Syndrome: A Significant Cause of Morbidity and Mortality , 2004, Circulation.

[51]  M. Goumans,et al.  Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells , 2004, The EMBO journal.

[52]  Paul S. Meltzer,et al.  Mutations in the human Jagged1 gene are responsible for Alagille syndrome , 1997, Nature Genetics.

[53]  M. Chin,et al.  The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation. , 2006, Journal of molecular and cellular cardiology.

[54]  M. H. Angelis,et al.  Maintenance of somite borders in mice requires the Delta homologue Dll1 , 1997, Nature.

[55]  Á. Raya,et al.  Activation of Notch signaling pathway precedes heart regeneration in zebrafish , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Randy L. Johnson,et al.  Targeted Disruption of hesr2 Results in Atrioventricular Valve Anomalies That Lead to Heart Dysfunction , 2004, Circulation research.

[57]  Thomas Gridley,et al.  A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. , 2002, Development.

[58]  A. Moorman,et al.  Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. , 2002, Genes & development.

[59]  R. Bodmer,et al.  Mesodermal cell fate decisions in Drosophila are under the control of the lineage genes numb, Notch, and sanpodo , 1998, Mechanisms of Development.

[60]  R. Beddington,et al.  Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. , 2002, Development.

[61]  R. Bodmer,et al.  Myogenic cells fates are antagonized by Notch only in asymmetric lineages of the Drosophila heart, with or without cell division , 2003, Development.

[62]  I. Krantz,et al.  NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. , 2006, American journal of human genetics.

[63]  S. Nishikawa,et al.  Activated Notch1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development , 2006, Mechanisms of Development.

[64]  Colin C. Collins,et al.  Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1 , 1997, Nature Genetics.

[65]  Raphael Kopan,et al.  γ-Secretase: proteasome of the membrane? , 2004, Nature Reviews Molecular Cell Biology.

[66]  Frank McCormick,et al.  Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. , 2004, Genes & development.

[67]  Hiroki Matsui,et al.  Jagged1-selective Notch Signaling Induces Smooth Muscle Differentiation via a RBP-Jκ-dependent Pathway* , 2006, Journal of Biological Chemistry.

[68]  T. Shirasawa,et al.  Presenilin 1 is essential for cardiac morphogenesis , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[69]  A. Fischer,et al.  Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors , 2006, Development.

[70]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[71]  L. Silver,et al.  Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development , 2004, Development.

[72]  S. Artavanis-Tsakonas,et al.  Crossing paths with Notch in the hyper-network. , 2007, Current opinion in cell biology.

[73]  A. Karsan,et al.  Smooth Muscle &agr;-Actin Is a Direct Target of Notch/CSL , 2006 .

[74]  M. Buckingham,et al.  Building the mammalian heart from two sources of myocardial cells , 2005, Nature Reviews Genetics.

[75]  G. Eichele,et al.  Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. , 2000, Developmental biology.

[76]  J. Erdmann,et al.  Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. , 2006, Biochemical and biophysical research communications.

[77]  Tasuku Honjo,et al.  Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. , 2004, Genes & development.

[78]  Janet Rossant,et al.  Dosage-sensitive requirement for mouse Dll4 in artery development. , 2004, Genes & development.

[79]  M. Keating,et al.  Heart Regeneration in Zebrafish , 2002, Science.

[80]  T. Rando,et al.  The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis. , 2005, Seminars in cell & developmental biology.

[81]  A. Fischer,et al.  Delta–Notch—and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors , 2007, Nucleic acids research.

[82]  T. Rando,et al.  The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. , 2002, Developmental cell.

[83]  J. Sundberg,et al.  Notch signaling is essential for vascular morphogenesis in mice. , 2000, Genes & development.

[84]  Judith S Eisen,et al.  Notch in the pathway: the roles of Notch signaling in neural crest development. , 2005, Seminars in cell & developmental biology.

[85]  L. Kedes,et al.  HERP, a New Primary Target of Notch Regulated by Ligand Binding , 2001, Molecular and Cellular Biology.

[86]  C. Bearzi,et al.  Stem cell niches in the adult mouse heart. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[87]  J. Epstein,et al.  Pursuing Cardiac Progenitors: Regeneration Redux , 2005, Cell.

[88]  D. Srivastava,et al.  HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. , 1999, Developmental biology.

[89]  H. Vanderstichele,et al.  Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[90]  C. Steidl,et al.  Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos , 2000, Mechanisms of Development.

[91]  A. Gossler,et al.  Premature myogenic differentiation and depletion of progenitor cells cause severe muscle hypotrophy in Delta1 mutants , 2007, Proceedings of the National Academy of Sciences.

[92]  M. Mercola,et al.  Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis. , 2000, Development.

[93]  Manfred Gessler,et al.  The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. , 2004, Genes & development.

[94]  Gavin Thurston,et al.  Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Larry Kedes,et al.  HES and HERP families: Multiple effectors of the notch signaling pathway , 2003, Journal of cellular physiology.

[96]  T. Kadesch,et al.  Notch signaling: the demise of elegant simplicity. , 2004, Current opinion in genetics & development.

[97]  K. Igarashi,et al.  Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse , 2006, Development.

[98]  Michael D. Schneider,et al.  BMP10 is essential for maintaining cardiac growth during murine cardiogenesis , 2004, Development.

[99]  Y. Saga,et al.  Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2 , 2007, Development.

[100]  M. Nemir,et al.  Induction of Cardiogenesis in Embryonic Stem Cells via Downregulation of Notch1 Signaling , 2006, Circulation research.

[101]  R. Bronson,et al.  The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis. , 2006, Genes & development.

[102]  A. Bernstein,et al.  Mice lacking both presenilin genes exhibit early embryonic patterning defects. , 1999, Genes & development.

[103]  Rüdiger Klein,et al.  Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor , 1995, Nature.

[104]  K. Fogarty,et al.  Notch signaling plays a key role in cardiac cell differentiation , 2006, Mechanisms of Development.

[105]  D. Srivastava,et al.  Hairy-related Transcription Factors Inhibit GATA-dependent Cardiac Gene Expression through a Signal-responsive Mechanism* , 2004, Journal of Biological Chemistry.

[106]  S. Nishikawa,et al.  Recombination signal sequence-binding protein Jκ alters mesodermal cell fate decisions by suppressing cardiomyogenesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[107]  J. Rossant,et al.  Notch1 is required for the coordinate segmentation of somites. , 1995, Development.

[108]  S. Fukumoto,et al.  Cardiovascular Basic Helix Loop Helix Factor 1, a Novel Transcriptional Repressor Expressed Preferentially in the Developing and Adult Cardiovascular System* , 2000, The Journal of Biological Chemistry.

[109]  R. Bronson,et al.  Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[110]  R R Markwald,et al.  Molecular regulation of atrioventricular valvuloseptal morphogenesis. , 1995, Circulation research.

[111]  G. Weinmaster,et al.  Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. , 2001, Development.

[112]  B. Klonjkowski,et al.  Notch 3 is required for arterial identity and maturation of vascular smooth muscle cells , 2004 .

[113]  S. Chiba Concise Review: Notch Signaling in Stem Cell Systems , 2006 .

[114]  A. Fischer,et al.  Mouse gridlock No Aortic Coarctation or Deficiency, but Fatal Cardiac Defects in Hey2 −/− Mice , 2002, Current Biology.