High levels of Cre expression in neuronal progenitors cause defects in brain development leading to microencephaly and hydrocephaly
High levels of Cre expression in neuronal progenitors cause defects in brain development leading to microencephaly and hydrocephaly
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DOI：
10.1523/jneurosci.2815-06.2006
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发表时间：
2006-09-13
影响因子：
5.3
通讯作者：
Ponzetto, Carola
中科院分区：
文献类型：
--
作者：
Forni, Paolo E.;Scuoppo, Claudio;Ponzetto, Carola
脑积水是一种常见的、多种多样的病理学，通常在怀孕期间受到基因毒性损伤后的新生儿中出现（Hicks 和 D'Amato，1980）。已知 Cre 重组酶可能具有毒性作用，会损害正常细胞周期和存活。在这里，我们通过使用三个独立的巢蛋白 Cre 转基因系表明，神经元祖细胞核中高水平的 Cre 重组酶表达会损害正常的大脑发育。分析的转基因品系是表达具有核定位信号的 Cre 重组酶的巢蛋白 Cre Balancer (Bal1) 系，以及两个巢蛋白 CreER(T2)（与截短的雌激素受体融合的 Cre 重组酶）小鼠系，其杂合 CreER(T2) 重组酶的表达水平不同，在他莫昔芬治疗后易位到细胞核中。所有纯合 Bal1 巢蛋白 Cre 胚胎均表现出神经元增殖减少、非整倍体和细胞死亡增加，以及室管膜衬里和皮质层压缺陷，导致小脑畸形和一种交通性脑积水。在他莫昔芬介导的 CreER(T2) 易位进入细胞核后，在两个巢蛋白 CreER(T2) 转基因系中观察到基本上重叠的表型。他莫昔芬处理的野生型小鼠和巢蛋白 CreER(T2) 油处理的对照小鼠均未表现出这些缺陷。这些结果表明某些形式的脑积水可能源自神经元前体增殖缺陷。此外，他们强调了神经源细胞中高水平核 Cre 的发育研究的潜在风险。
Hydrocephalus is a common and variegated pathology often emerging in newborn children after genotoxic insults during pregnancy (Hicks and D'Amato, 1980). Cre recombinase is known to have possible toxic effects that can compromise normal cell cycle and survival. Here we show, by using three independent nestin Cre transgenic lines, that high levels of Cre recombinase expression into the nucleus of neuronal progenitors can compromise normal brain development. The transgenics analyzed are the nestin Cre Balancer (Bal1) line, expressing the Cre recombinase with a nuclear localization signal, and two nestin CreER(T2) (Cre recombinase fused with a truncated estrogen receptor) mice lines with different levels of expression of a hybrid CreER(T2) recombinase that translocates into the nucleus after tamoxifen treatment. All homozygous Bal1 nestin Cre embryos displayed reduced neuronal proliferation, increased aneuploidy and cell death, as well as defects in ependymal lining and lamination of the cortex, leading to microencephaly and to a form of communicating hydrocephalus. An essentially overlapping phenotype was observed in the two nestin CreER(T2) transgenic lines after tamoxifen mediated CreER(T2) translocation into the nucleus. Neither tamoxifen-treated wild-type nor nestin CreER(T2) oil-treated control mice displayed these defects. These results indicate that some forms of hydrocephalus may derive from a defect in neuronal precursors proliferation. Furthermore, they underscore the potential risks for developmental studies of high levels of nuclear Cre in neurogenic cells.