Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.
Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.
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DOI：
10.1038/onc.2012.248
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发表时间：
2013-05-02
期刊：
影响因子：
8
通讯作者：
Gershon, T. R.
中科院分区：
文献类型：
--
作者：
Garcia, I.;Crowther, A. J.;Gama, V.;Miller, C. Ryan;Deshmukh, M.;Gershon, T. R.
神经发生需要通过祖细胞的分化或其程序性细胞死亡（PCD）进行负调节。生长调节在出生后的小脑中特别重要，在那里过度的祖细胞增殖促进髓母细胞瘤，这是儿童中最常见的恶性脑肿瘤。我们目前的证据表明，PCD的分化一起运作，以调节小脑颗粒神经元祖细胞（CGNP），并防止髓母细胞瘤。在这里，我们表明，基因缺失促凋亡Bax破坏小脑神经发生的调节，促进髓母细胞瘤的形成。在Bax−/−小鼠中，神经发生期延长到出生后第三周，异位神经元和祖细胞聚集在小脑和邻近顶盖的分子层中。重要的是，Bax基因的缺失在髓母细胞瘤倾向的ND 2：SmoA 1转基因小鼠大大加速肿瘤的发生。神经营养不良的髓母细胞瘤表现出明显不同的病理，细胞凋亡减少，神经分化和顶盖迁移增加。比较Bax+/+和Bax−/−髓母细胞瘤，我们能够确定Bcl-2的上调和p27的核排斥作为减轻Bax的肿瘤抑制作用所需的致瘤性变化。对人类肿瘤的研究证实了调节Bax在髓母细胞瘤发病机制中的重要性。我们的研究结果表明，神经元依赖性细胞凋亡调节出生后小脑神经发生，抑制髓母细胞瘤的形成，并施加选择性压力的肿瘤的形式。对髓母细胞瘤肿瘤发生所需的细胞凋亡的功能性抵抗可能是一种可用于治疗益处的肿瘤特异性脆弱性。
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax−/− mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax+/+ and Bax−/− medulloblastomas, we were able to identify up-regulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation, and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
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