title: Inappropriate p53 activation during development induces features of CHARGE syndrome.
abstract: CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.
authors.affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jeanine L
authors.initials: JL
authors.lastname: Van Nostrand
authors.affiliation: 1] Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA (C.A.B.); Department of Medicine, University of Central Florida, Orlando, Florida 32827, USA (M.M.K.); Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA (T.M.J.).
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Brady
authors.affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Heiyoun
authors.initials: H
authors.lastname: Jung
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Fuentes
authors.affiliation: 1] Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA (C.A.B.); Department of Medicine, University of Central Florida, Orlando, Florida 32827, USA (M.M.K.); Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA (T.M.J.).
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kozak
authors.affiliation: 1] Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA (C.A.B.); Department of Medicine, University of Central Florida, Orlando, Florida 32827, USA (M.M.K.); Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA (T.M.J.).
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Chien-Jung
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Swiderski
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: 1] Département de Génétique, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France [2] Unite INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.affiliation: Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ching-Pin
authors.initials: CP
authors.lastname: Chang
authors.affiliation: 1] Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wysocka
authors.affiliation: 1] Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Human Genetics, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.affiliation: 1] Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D058747:CHARGE Syndrome / Q000235:genetics* / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004423:Ear / Q000002:abnormalities; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53