Sonntag Kai-Christian, Simantov Rabi, Björklund Lars, Cooper Oliver, Pruszak Jan, Kowalke Florian, Gilmartin Jocelyn, Ding Jixiang, Hu Ya-Ping, Shen Michael M, Isacson Ole
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
Mol Cell Neurosci. 2005 Mar;28(3):417-29. doi: 10.1016/j.mcn.2004.06.003.
Activation of transforming growth factor-beta (TGF-beta) receptors typically elicits mesodermal development, whereas inhibition of this pathway induces neural fates. In vitro differentiated mouse embryonic stem (ES) cells with deletion of the TGF-beta pathway-related factors Smad4 or Cripto exhibited increased numbers of neurons. Cripto-/- ES cells developed into neuroecto-/epidermal cell types, while Smad4-/- cells also displayed mesodermal differentiation. ES cell differentiation into catecholaminergic neurons showed that these ES cells retained their ability to develop into dopaminergic and serotonergic neurons with typical expression patterns of midbrain and hindbrain genes. In vivo, transplanted ES cells to the mouse striatum became small neuronal grafts, or large grafts with cell types from all germ layers independent of their ES cell genotype. This demonstrates that Smad4-/- and Cripto-/- ES cells favor a neural fate in vitro, but also express the mesodermal phenotype, implying that deletion of either Smad4 or Cripto is not sufficient to block nonneuronal tissue formation.
转化生长因子-β（TGF-β）受体的激活通常会引发中胚层发育，而抑制该信号通路则会诱导神经命运的形成。在体外分化的缺失TGF-β信号通路相关因子Smad4或Cripto的小鼠胚胎干细胞（ES细胞）中，神经元数量增加。Cripto基因敲除的ES细胞发育为神经外胚层/表皮细胞类型，而Smad4基因敲除的细胞也表现出中胚层分化。ES细胞向儿茶酚胺能神经元的分化表明，这些ES细胞保留了发育为多巴胺能和5-羟色胺能神经元的能力，并具有中脑和后脑基因的典型表达模式。在体内，将ES细胞移植到小鼠纹状体后，会形成小型神经移植物，或形成包含所有胚层细胞类型的大型移植物，且这与ES细胞的基因型无关。这表明，Smad4基因敲除和Cripto基因敲除的ES细胞在体外倾向于神经命运，但也表达中胚层表型，这意味着单独缺失Smad4或Cripto不足以阻止非神经组织的形成。
