Licensing regulators Geminin and Cdt1 identify progenitor cells of the mouse CNS in a specific phase of the cell cycle
Licensing regulators Geminin and Cdt1 identify progenitor cells of the mouse CNS in a specific phase of the cell cycle
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DOI：
10.1016/j.neuroscience.2007.03.050
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发表时间：
2007-06
期刊：
影响因子：
3.3
通讯作者：
M. Spella;O. Britz;Panorea Kotantaki;Z. Lygerou;H. Nishitani;R. Ramsay;C. Flordellis;F. Guillemot;T. Mantamadiotis;S. Taraviras
中科院分区：
文献类型：
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作者：
M. Spella;O. Britz;Panorea Kotantaki;Z. Lygerou;H. Nishitani;R. Ramsay;C. Flordellis;F. Guillemot;T. Mantamadiotis;S. Taraviras
神经系统形成整合了细胞增殖和分化的控制，并由多能神经祖细胞介导，所述多能神经祖细胞在产生分化的神经元和神经胶质细胞之前逐渐限制其发育潜力。来自不同实验系统的证据表明，Geminin是神经系统发育过程中连接增殖和分化的候选分子。我们发现，Geminin及其结合伙伴Cdt 1在小鼠神经发生早期的神经前体细胞中大量表达。它们的表达水平在发育后期下降，在分化后变得不可检测。表达Geminin和Cdt 1的细胞也表达Sox 2，而与表达分化的神经元表型的标志物的细胞没有检测到重叠。表达RC 2和Pax 6的放射状胶质细胞的一部分也对Geminin和Cdt 1具有免疫反应性。大多数Geminin和Cdt 1表达细胞群似乎与表达Mash 1或Neurogenin 2的命运限制性前体细胞不同。溴脱氧尿苷（BrdU）掺入实验揭示了神经祖细胞中的细胞周期特异性表达，其中Geminin存在于S至M期，而Cdt 1表达表征G1期祖细胞。此外，成人神经球培养物的体外分化显示在分化状态下Geminin/Cdt 1的下调，与我们的数据一致，该数据显示Geminin存在于小鼠胚胎发生和成年期间CNS的神经祖细胞中，并且在细胞命运特化和分化后下调。这表明Geminin在神经前体细胞的形成和维持中的作用。
Nervous system formation integrates control of cellular proliferation and differentiation and is mediated by multipotent neural progenitor cells that become progressively restricted in their developmental potential before they give rise to differentiated neurons and glial cells. Evidence from different experimental systems suggests that Geminin is a candidate molecule linking proliferation and differentiation during nervous system development. We show here that Geminin and its binding partner Cdt1 are expressed abundantly by neural progenitor cells during early mouse neurogenesis. Their expression levels decline at late developmental stages and become undetectable upon differentiation. Geminin and Cdt1 expressing cells also express Sox2 while no overlap is detected with cells expressing markers of a differentiated neuronal phenotype. A fraction of radial glial cells expressing RC2 and Pax6 are also immunoreactive for Geminin and Cdt1. The majority of the Geminin and Cdt1 expressing cell populations appears to be distinct from fate-restricted precursor cells expressing Mash1 or Neurogenin2. Bromo-deoxy-uridine (BrdU) incorporation experiments reveal a cell cycle specific expression in neural progenitor cells, with Geminin being present from S to M phase, while Cdt1 expression characterizes progenitor cells in G1 phase. Furthermore, in vitro differentiation of adult neurosphere cultures shows downregulation of Geminin/Cdt1 in the differentiated state, in line with our data showing that Geminin is present in neural progenitor cells of the CNS during mouse embryogenesis and adulthood and becomes downregulated upon cell fate specification and differentiation. This suggests a role for Geminin in the formation and maintenance of the neural progenitor cells.