Cavallaro Maurizio, Mariani Jessica, Lancini Cesare, Latorre Elisa, Caccia Roberta, Gullo Francesca, Valotta Menella, DeBiasi Silvia, Spinardi Laura, Ronchi Antonella, Wanke Enzo, Brunelli Silvia, Favaro Rebecca, Ottolenghi Sergio, Nicolis Silvia K
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
Development. 2008 Feb;135(3):541-57. doi: 10.1242/dev.010801. Epub 2008 Jan 2.
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.
转录因子Sox2在神经干细胞中具有活性，Sox2“敲低”小鼠在海马体和眼睛的神经干/祖细胞中表现出缺陷，可能在一些神经元中也有缺陷。在人类中，杂合性Sox2缺乏与眼部异常、海马体畸形和癫痫有关。为了更好地理解Sox2的作用，我们对从“敲低”突变体的胚胎和成年大脑中培养的神经干细胞进行了体外分化研究。Sox2在未分化细胞中表达较高，并随着分化而下降，但在至少一些成熟神经元中仍可见。在突变细胞中，神经元分化受到严重影响，而星形胶质细胞分化未受影响。β-微管蛋白阳性细胞丰富，但大多数未能发育成更成熟的神经元，并表现出形态异常。在分化早期而非晚期的神经细胞中过表达Sox2可挽救神经元成熟缺陷。此外，它还抑制了神经胶质细胞中GFAP的表达。我们的结果表明，在体外，早期分化的神经元谱系细胞的成熟以及替代谱系标记的抑制需要Sox2。最后，我们检查了来自Sox2“敲低”新生和成年小鼠的新生成神经元。新生小鼠皮质和成年嗅球中的GABA能神经元数量大大减少，一些神经元表现出异常的形态和迁移特性。GABA缺乏可能是一些敲低小鼠以及SOX2缺陷个体中观察到的癫痫的一个合理原因。
