Department of Neurology, Medical Faculty, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
Development. 2012 Sep;139(18):3306-15. doi: 10.1242/dev.074518. Epub 2012 Aug 8.
Our recent studies revealed p57kip2 as an intrinsic regulator of late gliogenesis and demonstrated that in oligodendroglial precursor cells p57kip2 inhibition leads to accelerated maturation. Adult neural stem cells have been described as a source of glial progenitors; however, the underlying mechanisms of cell fate specification are still poorly understood. Here, we have investigated whether p57kip2 can influence early events of glial determination and differentiation. We found that Sox2/GFAP double-positive cells express p57kip2 in stem cell niches of the adult brain. Short-hairpin RNA-mediated suppression of p57kip2 in cultured adult neural stem cells was found to strongly reduce astroglial characteristics, while oligodendroglial precursor features were increased. Importantly, this anti-astrogenic effect of p57kip2 suppression dominated the bone morphogenetic protein-mediated promotion of astroglial differentiation. Moreover, we observed that in p57kip2 knockdown cells, the BMP antagonist chordin was induced. Finally, when p57kip2-suppressed stem cells were transplanted into the adult spinal cord, fewer GFAP-positive cells were generated and oligodendroglial markers were induced when compared with control cells, demonstrating an effect of in vivo relevance.
我们最近的研究揭示了 p57kip2 是晚期神经胶质发生的内在调节因子，并表明在少突胶质前体细胞中，p57kip2 的抑制会导致成熟加速。成体神经干细胞被描述为神经胶质前体细胞的来源；然而，细胞命运特化的潜在机制仍知之甚少。在这里，我们研究了 p57kip2 是否可以影响胶质决定和分化的早期事件。我们发现 Sox2/GFAP 双阳性细胞在成年大脑的干细胞龛中表达 p57kip2。短发夹 RNA 介导的 p57kip2 抑制在培养的成年神经干细胞中被发现强烈降低了星形胶质细胞特征，而少突胶质前体细胞特征增加。重要的是，p57kip2 抑制的这种抗星形胶质细胞作用主导了骨形态发生蛋白介导的星形胶质细胞分化的促进。此外，我们观察到在 p57kip2 敲低细胞中，BMP 拮抗剂 chordin 被诱导。最后，当 p57kip2 抑制的干细胞被移植到成年脊髓中时，与对照细胞相比，产生的 GFAP 阳性细胞较少，并且诱导了少突胶质细胞标记物，表明存在体内相关性。
