Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants
Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants
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DOI：
10.1242/dev.010801
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发表时间：
2008-02-01
期刊：
影响因子：
4.6
通讯作者：
Nicolis, Silvia K.
中科院分区：
文献类型：
--
作者：
Cavallaro, Maurizio;Mariani, Jessica;Nicolis, Silvia K.
转录因子 Sox2 在神经干细胞中活跃，Sox2“敲除”小鼠的海马体和眼睛的神经干/祖细胞以及可能的一些神经元中显示出缺陷。在人类中，杂合性 Sox2 缺陷与眼睛异常、海马畸形和癫痫有关。为了更好地了解 Sox2 的作用，我们对从“敲低”突变体的胚胎和成人大脑中培养的神经干细胞进行了体外分化研究。 Sox2 表达在未分化细胞中较高，并随着分化而下降，但至少在一些成熟神经元中仍然可见。在突变细胞中，神经元（而非星形胶质细胞）的分化受到深刻影响。 β-微管蛋白阳性细胞数量丰富，但大多数未能进展为更成熟的神经元，并表现出形态异常。 Sox2在神经细胞分化早期而不是晚期的过度表达可以挽救神经元成熟缺陷。此外，它还抑制神经胶质细胞中的 GFAP 表达。我们的结果表明，早期分化的神经元谱系细胞在体外需要 Sox2，以实现成熟和抑制替代谱系标记。最后，我们检查了 Sox2“敲除”的新生和成年小鼠新产生的神经元。新生小鼠皮层和成年嗅球中的 GABA 能神经元数量大大减少，并且一些神经元表现出异常的形态和迁移特性。 GABA 缺乏是在一些基因敲除小鼠以及 SOX2 缺陷个体中观察到的癫痫的合理解释。
The transcription factor Sox2 is active in neural stem cells, and Sox2 ' knockdown' mice show defects in neural stem/ progenitor cells in the hippocampus and eye, and possibly some neurons. In humans, heterozygous Sox2 deficiency is associated with eye abnormalities, hippocampal malformation and epilepsy. To better understand the role of Sox2, we performed in vitro differentiation studies on neural stem cells cultured from embryonic and adult brains of ' knockdown' mutants. Sox2 expression is high in undifferentiated cells, and declines with differentiation, but remains visible in at least some of the mature neurons. In mutant cells, neuronal, but not astroglial, differentiation was profoundly affected. beta- Tubulin- positive cells were abundant, but most failed to progress to more mature neurons, and showed morphological abnormalities. Overexpression of Sox2 in neural cells at early, but not late, stages of differentiation, rescued the neuronal maturation defect. In addition, it suppressed GFAP expression in glial cells. Our results show an in vitro requirement for Sox2 in early differentiating neuronal lineage cells, for maturation and for suppression of alternative lineage markers. Finally, we examined newly generated neurons from Sox2 ' knockdown' newborn and adult mice. GABAergic neurons were greatly diminished in number in newborn mouse cortex and in the adult olfactory bulb, and some showed abnormal morphology and migration properties. GABA deficiency represents a plausible explanation for the epilepsy observed in some of the knockdown mice, as well as in SOX2- deficient individuals.