title: MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1.
abstract: Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Ralston M
authors.initials: RM
authors.lastname: Barnes
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Harris
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jaehnig
authors.affiliation: Cardiovascular Developmental Biology Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sauls
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Sinha
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Anabel
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: William
authors.initials: W
authors.lastname: Schachterle
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: McCulley
authors.affiliation: Cardiovascular Developmental Biology Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA brian.black@ucsf.edu.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics; D006345:Heart Septal Defects, Ventricular / Q000235:genetics; D006352:Heart Ventricles; D006801:Humans; D017403:In Situ Hybridization; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009024:Morphogenesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D038081:Organogenesis; D017423:Sequence Analysis, RNA; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014188:Transposition of Great Vessels / Q000235:genetics
chemical_list: D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C489450:Tdgf1 protein, mouse; D004815:Epidermal Growth Factor
keywords: Cripto; Enhancer; Heart development; MEF2; Mouse; Tdgf1
references.citation: Semin Cell Dev Biol. 2007 Feb;18(1):67-76
references.pmid: 17276708
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Dev Cell. 2004 Sep;7(3):331-45
references.pmid: 15363409
references.citation: Am J Hum Genet. 2008 Jul;83(1):18-29
references.pmid: 18538293
references.citation: Genesis. 2005 Apr;41(4):192-201
references.pmid: 15789410
references.citation: Methods Mol Biol. 2009;530:423-33
references.pmid: 19266333
references.citation: Development. 2004 Aug;131(16):3931-42
references.pmid: 15253934
references.citation: Cell. 2008 Dec 12;135(6):1053-64
references.pmid: 19070576
references.citation: Nature. 1998 Oct 15;395(6703):702-7
references.pmid: 9790191
references.citation: Curr Top Dev Biol. 2012;100:33-65
references.pmid: 22449840
references.citation: Pediatr Cardiol. 2010 Apr;31(3):430-7
references.pmid: 20165841
references.citation: BMC Bioinformatics. 2008;9:523
references.pmid: 19061503
references.citation: Dev Dyn. 2011 Jan;240(1):195-203
references.pmid: 21089073
references.citation: Dev Biol. 2000 Nov 15;227(2):495-509
references.pmid: 11071769
references.citation: Development. 1999 Feb;126(3):483-94
references.pmid: 9876177
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: Nature. 2012 Sep 6;489(7414):75-82
references.pmid: 22955617
references.citation: Br Heart J. 1974 Oct;36(10):948-70
references.pmid: 4433452
references.citation: Dev Dyn. 2008 Nov;237(11):3200-9
references.pmid: 18924235
references.citation: J Mol Cell Cardiol. 2011 Jul;51(1):58-66
references.pmid: 21382375
references.citation: Dev Biol. 2006 Aug 15;296(2):437-49
references.pmid: 16836994
references.citation: Nature. 2000 Jan 27;403(6768):385-9
references.pmid: 10667782
references.citation: Am J Hum Genet. 2015 Feb 5;96(2):235-44
references.pmid: 25658046
references.citation: Genesis. 2001 Dec;31(4):176-80
references.pmid: 11783008
references.citation: Wiley Interdiscip Rev Dev Biol. 2013 Jul;2(4):499-530
references.pmid: 24014420
references.citation: Int J Cardiol. 2011 Jan 21;146(2):225-7
references.pmid: 19853938
references.citation: Genesis. 2005 Sep;43(1):43-8
references.pmid: 16106363
references.citation: Nat Genet. 2000 Mar;24(3):262-5
references.pmid: 10700179
references.citation: Annu Rev Genomics Hum Genet. 2003;4:1-32
references.pmid: 12730129
references.citation: Circ Res. 2014 Oct 10;115(9):790-9
references.pmid: 25190705
references.citation: Cardiol Young. 2013 Dec;23(6):858-66
references.pmid: 24401259
references.citation: J Cardiovasc Magn Reson. 2006;8(4):645-59
references.pmid: 16869316
references.citation: J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900
references.pmid: 12084585
references.citation: Science. 1997 May 30;276(5317):1404-7
references.pmid: 9162005
references.citation: Dev Biol. 2012 Oct 1;370(1):135-44
references.pmid: 22841628
references.citation: Development. 2005 Aug;132(15):3405-17
references.pmid: 15987774
references.citation: J Clin Exp Cardiolog. 2012;Suppl 11:1-4
references.pmid: 24069547
references.citation: Hum Mol Genet. 2009 Mar 1;18(5):861-71
references.pmid: 19064609
references.citation: Mol Cell Biol. 2002 Jul;22(13):4439-49
references.pmid: 12052855
references.citation: Dev Biol. 2005 Nov 1;287(1):134-45
references.pmid: 16188249
references.citation: Circ J. 2012;76(7):1703-11
references.pmid: 22498567
references.citation: Methods Mol Biol. 2006;338:69-89
references.pmid: 16888351
references.citation: J Cardiovasc Dev Dis. 2015;2(2):108-124
references.pmid: 26878022
references.citation: Skelet Muscle. 2015 Feb 27;5:7
references.pmid: 25789156
references.citation: Trends Genet. 2000 Jul;16(7):303-9
references.pmid: 10858660
references.citation: Development. 2007 Mar;134(6):1023-34
references.pmid: 17287255
references.citation: Dev Biol. 2004 Mar 1;267(1):190-202
references.pmid: 14975726