Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors
Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors
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DOI：
10.1038/s41467-019-09949-6
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发表时间：
2019-05-01
影响因子：
16.6
通讯作者：
Chan, Jennifer A.
中科院分区：
文献类型：
--
作者：
Ahmad, Shiekh Tanveer;Rogers, Alexandra D.;Chan, Jennifer A.
Capicua（Cic）是一种在脑肿瘤少突胶质细胞瘤中突变的转录抑制因子。尽管它与癌症有关，但人们对Cic在大脑中的功能知之甚少。我们发现，核Cic表达是最强的星形胶质细胞和神经元，但较弱的干细胞和oligodendroglial谱系细胞。使用一种新的条件性Cic敲除小鼠，我们证明了前脑特异性Cic缺失增加了神经干细胞的增殖和自我更新。此外，Cic损失使神经干细胞偏向于胶质细胞谱系选择，从而扩大少突胶质细胞前体细胞（OPCs）的库。这些增殖和谱系效应依赖于Ets转录因子的去抑制。在患者来源的少突胶质细胞瘤细胞中，CIC再表达或ETV5阻断降低谱系偏倚、增殖、自我更新和致瘤性。我们的研究结果确定Cic作为神经发育和少突胶质细胞瘤中细胞命运的重要调节因子，并表明其损失有助于少突胶质细胞瘤通过Ets过度活性促进增殖和OPC样身份。
Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic's function in the brain. We show that nuclear Cic expression is strongest in astrocytes and neurons but weaker in stem cells and oligoden-droglial lineage cells. Using a new conditional Cic knockout mouse, we demonstrate that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage effects are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal, and tumorigenicity. Our results identify Cic as an important regulator of cell fate in neuro-development and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.