Spella M, Britz O, Kotantaki P, Lygerou Z, Nishitani H, Ramsay R G, Flordellis C, Guillemot F, Mantamadiotis T, Taraviras S
Department of Pharmacology, School of Medicine, University of Patras, 26500 Rio, Patras, Greece.
Neuroscience. 2007 Jun 29;147(2):373-87. doi: 10.1016/j.neuroscience.2007.03.050. Epub 2007 May 29.
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.
神经系统的形成整合了对细胞增殖和分化的控制，由多能神经祖细胞介导，这些祖细胞在产生分化的神经元和胶质细胞之前，其发育潜能逐渐受到限制。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。我们在此表明，在小鼠早期神经发生过程中，神经祖细胞大量表达Geminin及其结合伴侣Cdt1。它们的表达水平在发育后期下降，分化时变得无法检测到。表达Geminin和Cdt1的细胞也表达Sox2，而与表达分化神经元表型标志物的细胞没有重叠。一部分表达RC2和Pax6的放射状胶质细胞对Geminin和Cdt1也有免疫反应。大多数表达Geminin和Cdt1的细胞群体似乎与表达Mash1或Neurogenin2的命运受限前体细胞不同。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，Geminin从S期到M期存在，而Cdt1的表达表征G1期的祖细胞。此外，成年神经球培养物的体外分化显示，在分化状态下Geminin/Cdt1下调，这与我们的数据一致，即Geminin在小鼠胚胎发育和成年期存在于中枢神经系统的神经祖细胞中，并在细胞命运特化和分化时下调。这表明Geminin在神经祖细胞的形成和维持中起作用。
