Quintes Susanne, Brinkmann Bastian G, Ebert Madlen, Fröb Franziska, Kungl Theresa, Arlt Friederike A, Tarabykin Victor, Huylebroeck Danny, Meijer Dies, Suter Ueli, Wegner Michael, Sereda Michael W, Nave Klaus-Armin
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
University Medical Center Göttingen (UMG), Department of Clinical Neurophysiology, Göttingen, Germany.
Nat Neurosci. 2016 Aug;19(8):1050-1059. doi: 10.1038/nn.4321. Epub 2016 Jun 13.
Schwann cell development and peripheral nerve myelination require the serial expression of transcriptional activators, such as Sox10, Oct6 (also called Scip or Pou3f1) and Krox20 (also called Egr2). Here we show that transcriptional repression, mediated by the zinc-finger protein Zeb2 (also known as Sip1), is essential for differentiation and myelination. Mice lacking Zeb2 in Schwann cells develop a severe peripheral neuropathy, caused by failure of axonal sorting and virtual absence of myelin membranes. Zeb2-deficient Schwann cells continuously express repressors of lineage progression. Moreover, genes for negative regulators of maturation such as Sox2 and Ednrb emerge as Zeb2 target genes, supporting its function as an 'inhibitor of inhibitors' in myelination control. When Zeb2 is deleted in adult mice, Schwann cells readily dedifferentiate following peripheral nerve injury and become repair cells. However, nerve regeneration and remyelination are both perturbed, demonstrating that Zeb2, although undetectable in adult Schwann cells, has a latent function throughout life.
施万细胞的发育和周围神经髓鞘形成需要转录激活因子的顺序表达，如Sox10、Oct6（也称为Scip或Pou3f1）和Krox20（也称为Egr2）。我们在此表明，由锌指蛋白Zeb2（也称为Sip1）介导的转录抑制对于分化和髓鞘形成至关重要。施万细胞中缺乏Zeb2的小鼠会发展出严重的周围神经病变，这是由轴突分选失败和髓鞘膜几乎缺失所致。Zeb2缺陷型施万细胞持续表达谱系进展的抑制因子。此外，诸如Sox2和Ednrb等成熟负调控因子的基因成为Zeb2的靶基因，支持其在髓鞘形成控制中作为“抑制剂的抑制剂”的功能。当在成年小鼠中删除Zeb2时，施万细胞在周围神经损伤后很容易去分化并成为修复细胞。然而，神经再生和髓鞘再生均受到干扰，这表明Zeb2尽管在成年施万细胞中无法检测到，但在整个生命过程中都具有潜在功能。
