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Inappropriate p53 activation during development induces features of CHARGE syndrome
Journal article   Open access   Peer reviewed

Inappropriate p53 activation during development induces features of CHARGE syndrome

Jeanine L Van Nostrand, Colleen A Brady, Heiyoun Jung, Daniel R Fuentes, Margaret M Kozak, Thomas M Johnson, Chieh-Yu Lin, Chien-Jung Lin, Donald L Swiderski, Hannes Vogel, …
Nature (London), Vol.514(7521), pp.228-232
10/09/2014
DOI: 10.1038/nature13585
PMCID: PMC4192026
PMID: 25119037
url
https://stars.library.ucf.edu/scopus2010/8117View
Open Access

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.
 Phenotype Abnormalities, Multiple - genetics Abnormalities, Multiple - metabolism Alleles Animals Apoptosis - genetics Cell Cycle Checkpoints - genetics CHARGE Syndrome - genetics CHARGE Syndrome - metabolism Craniofacial Abnormalities - genetics Craniofacial Abnormalities - metabolism DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Ear - abnormalities Embryo, Mammalian - abnormalities Embryo, Mammalian - metabolism Female Fibroblasts Gene Deletion Heterozygote Humans Male Mice Mutant Proteins - metabolism Promoter Regions, Genetic - genetics Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism

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