Inappropriate p53 activation during development induces features of CHARGE syndrome.
Inappropriate p53 activation during development induces features of CHARGE syndrome.
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DOI：
10.1038/nature13585
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发表时间：
2014-10-09
期刊：
影响因子：
64.8
通讯作者：
Attardi, Laura D.
中科院分区：
文献类型：
--
作者：
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.;Attie-Bitach, Tania;Chang, Ching-Pin;Wysocka, Joanna;Martin, Donna M.;Attardi, Laura D.
CHARGE综合征是一种多发性异常疾病，患者表现为多种表型，包括眼缺损、心脏缺陷、后鼻孔闭锁、生长发育迟缓、泌尿生殖系统发育不全和耳畸形。尽管70-90%的CHARGE综合征病例是由编码ATP依赖性染色质重塑因子的CHD 7基因突变引起的，但对不同表型的潜在途径仍然知之甚少。令人惊讶的是，我们对一种表达肿瘤抑制蛋白p53的稳定和转录死亡变体的敲入突变小鼠品系的研究（p5325，26，53，54），沿着p53的野生型等位基因（也称为Trp 53），揭示了与CHARGE综合征特征性的许多表型相关的妊娠晚期胚胎致死性，包括缺损，内耳和外耳畸形、心脏流出道缺陷和颅面缺陷。我们发现，p5325，26，53，54突变蛋白稳定和过度激活野生型p53，然后不适当地诱导其靶基因，并触发细胞周期停滞或凋亡在发育过程中。重要的是，这些表型仅在野生型p53等位基因中观察到，asp 5325，26，53，54/−胚胎完全存活。此外，我们发现CHD 7可以与p53启动子结合，从而负调节p53表达，并且CHD 7在小鼠神经嵴细胞或CHARGE综合征患者样本中的缺失导致p53激活。引人注目的是，我们发现p53杂合性部分挽救了Chd 7缺失小鼠胚胎的表型，表明p53有助于CHD 7缺失导致的表型。因此，发育过程中不适当的p53激活可以促进CHARGE表型，支持p53在发育综合征中起关键作用的观点，并为CHARGE综合征的潜在机制提供重要的见解。
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 geneCHD7, 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 (p5325,26,53,54), along with a wild-type allele ofp53(also known asTrp53), 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 p5325,26,53,54mutant 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-typep53allele, asp5325,26,53,54/−embryos were fully viable. Furthermore, we found that CHD7 can bind to thep53promoter, thereby negatively regulatingp53expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found thatp53heterozygosity partially rescued the phenotypes inChd7-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.
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