ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation
ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation
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DOI：
10.1242/dev.139022
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发表时间：
2016-11-01
期刊：
影响因子：
4.6
通讯作者：
Gershon, Timothy R.
中科院分区：
文献类型：
--
作者：
Lang, Patrick Y.;Nanjangud, Gouri J.;Gershon, Timothy R.
小头畸形和髓母细胞瘤都可能是由于基因突变破坏了基因组的稳定性。我们报告说，ATR，这是突变的小头症塞克尔综合征，维持小脑生长，通过维持染色体的完整性，在出生后的神经发生。小脑颗粒神经元前体细胞（CGNP）中Atr缺失诱导小鼠增殖相关DNA损伤、p53激活、凋亡和小脑发育不良。p53或Bax和巴克的共同缺失阻止了Atr缺失的CGNP的凋亡，但未能完全挽救小脑的生长。ATR缺陷的CGNP具有受损的细胞周期检查点功能，并继续增殖，积累染色体异常。RNA-Seq证明，对ATR缺陷增殖的转录应答是高度依赖于p53的，并且通过p53共缺失而显著减弱。通过纳米颗粒配制的VE-822的体内急性ATR抑制再现了Atr缺失所见的发育破坏。Atr基因缺失阻断了髓母细胞瘤易感SmoM 2小鼠的肿瘤发生我们的数据表明，p53驱动的细胞凋亡和细胞周期停滞-以及在没有p53的情况下，非凋亡性细胞死亡-冗余地限制ATR缺陷祖细胞的生长。这些机制可用于使用ATR抑制治疗CGNP衍生的髓母细胞瘤。
Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastoma-prone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest - and, in the absence of p53, non-apoptotic cell death - redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition.