title: Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development.
abstract: Patients with Down syndrome have characteristic heart valve lesions resulting from endocardial cushion defects. The Down syndrome critical region 1 (DSCR1) gene, identified at the conserved trisomic 21 region in those patients, encodes a calcineurin inhibitor that inactivates nuclear factor of activated T cells (NFATc) activity. Here, we identify a regulatory sequence in the promoter region of human DSCR1 that dictates specific expression of a reporter gene in the endocardium, defined by the temporal and spatial expression of Nfatc1 during heart valve development. Activation of this evolutionally conserved DSCR1 regulatory sequence requires calcineurin and NFATc1 signaling in the endocardium. NFATc1 proteins bind to the regulatory sequence and trigger its enhancer activity. NFATc1 is sufficient to induce the expression of Dscr1 in cells that normally have undetectable or minimal NFATc1 or DSCR1. Pharmacologic inhibition of calcineurin or genetic Nfatc1 null mutation in mice abolishes the endocardial activity of this DSCR1 enhancer. Furthermore, in mice lacking endocardial NFATc1, the endogenous Dscr1 expression is specifically inhibited in the endocardium but not in the myocardium. Thus, our studies indicate that the DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the endocardium during a critical window of heart valve formation.
authors: Department of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Hai
authors: H
authors: Wu
authors: Shih-chu
authors: SC
authors: Kao
authors: Tomasa
authors: T
authors: Barrientos
authors: Scott H
authors: SH
authors: Baldwin
authors: Eric N
authors: EN
authors: Olson
authors: Gerald R
authors: GR
authors: Crabtree
authors: Bin
authors: B
authors: Zhou
authors: Ching-Pin
authors: CP
authors: Chang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004699:Endocardium / Q000196:embryology* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006352:Heart Ventricles / Q000002:abnormalities / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; C108612:RCAN1 protein, human; D019703:Calcineurin
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