Inappropriate p53 activation during development induces features of CHARGE syndrome

• Published in: Nature (London) Vol. 514; no. 7521; pp. 228 - 232
• Main Authors: Van Nostrand, Jeanine L., Brady, Colleen A., Jung, Heiyoun, Fuentes, Daniel R., Kozak, Margaret M., Johnson, Thomas M., Lin, Chieh-Yu, Lin, Chien-Jung, Swiderski, Donald L., Vogel, Hannes, Bernstein, Jonathan A., Attié-Bitach, Tania, Chang, Ching-Pin, Wysocka, Joanna, Martin, Donna M., Attardi, Laura D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-10-2014; Nature Publishing Group
• Subjects: 13; 13/100; 13/106; 13/109; 13/2; 13/51; 14; 14/63; 38; 38/77; 45/15; 45/90; 631/136/1455; 631/67/581; 631/67/68; 64/60; 82/1; 82/80; Abnormalities, Multiple - genetics; Abnormalities, Multiple - metabolism; Alleles; Animals; Apoptosis; Apoptosis - genetics; Care and treatment; Cell Cycle Checkpoints - genetics; Charge syndrome; CHARGE Syndrome - genetics; CHARGE Syndrome - metabolism; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - metabolism; Defects; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Ear - abnormalities; Embryo, Mammalian - abnormalities; Embryo, Mammalian - metabolism; Embryonic development; Embryos; Female; Fibroblasts; Gene Deletion; Gene expression; Heart; Heterozygote; Humanities and Social Sciences; Humans; letter; Male; Mice; multidisciplinary; Mutant Proteins - metabolism; Mutation; Phenotype; Physiological aspects; Promoter Regions, Genetic - genetics; Proteins; Risk factors; Rodents; Science; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13585

Inappropriate activation of the tumour-suppressor protein p53 during development can promote phenotypes similar to those of CHARGE syndrome, suggesting that p53 activation not only has a beneficial function in suppressing cancer but also a deleterious function in promoting developmental syndromes.
CHARGE syndrome promoted by activated p53
The complex congenital disorder known as CHARGE syndrome results in many phenotypes, including heart defects, retarded growth and development, genital hypoplasia and ear abnormalities. Most CHARGE syndrome patients have mutations in the gene for the chromatin remodeller protein CHD7, but in mouse the
Chd7
mutation is embryonically lethal, and not all CHARGE syndrome phenotypes are evident.
Laura Attardi and colleagues now demonstrate that inappropriate activation of the
p53
tumour suppressor gene during development can promote CHARGE phenotypes in mice, including ocular coloboma and defects of both the outer and inner ear, which are typical of CHARGE syndrome and rare in other conditions. The findings that
p53
mutations can drive both cancer and developmental diseases throws a new light on the function of p53
in vivo
.
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
1
. 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
2
. 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
)
3
, 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.