Fukui Hirokazu, Rünker Annette, Fabel Klaus, Buchholz Frank, Kempermann Gerd
German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany.
CRTD-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
PLoS One. 2018 Jan 11;13(1):e0190789. doi: 10.1371/journal.pone.0190789. eCollection 2018.
Transcription factor Runx1 (Runt Related Transcription Factor 1), plays an important role in the differentiation of hematopoetic stem cells, angiogenesis and the development of nociceptive neurons. These known functions have in common that they relate to lineage decisions. We thus asked whether such role might also be found for Runx1 in adult hippocampal neurogenesis as a process, in which such decisions have to be regulated lifelong. Runx1 shows a widespread low expression in the adult mouse brain, not particularly prominent in the hippocampus and the resident neural precursor cells. Isoforms 1 and 2 of Runx1 (but not 3 to 5) driven by the proximal promoter were expressed in hippocampal precursor cells ex vivo, albeit again at very low levels, and were markedly increased after stimulation with TGF-β1. Under differentiation conditions (withdrawal of growth factors) Runx1 became down-regulated. Overexpression of Runx1 in vitro reduced proliferation, increased survival of precursor cells by reducing apoptosis, and increased neuronal differentiation, while slightly reducing dendritic morphology and complexity. Transfection with dominant-negative Runx1 in hippocampal precursor cells in vitro did not result in differences in neurogenesis. Hippocampal expression of Runx1 correlated with adult neurogenesis (precursor cell proliferation) across BXD recombinant strains of mice and covarying transcripts enriched in the GO categories "neural precursor cell proliferation" and "neuron differentiation". Runx1 is thus a plausible candidate gene to be involved in regulating initial differentiation-related steps of adult neurogenesis. It seems, however, that the relative contribution of Runx1 to such effect is complementary and will explain only small parts of the cell-autonomous pro-differentiation effect.
转录因子Runx1（Runt相关转录因子1）在造血干细胞分化、血管生成和伤害感受神经元发育中发挥重要作用。这些已知功能的共同之处在于它们与谱系决定有关。因此，我们不禁要问，Runx1在成体海马神经发生过程中是否也具有这样的作用，因为在这个过程中，此类决定必须终身受到调控。Runx1在成年小鼠大脑中广泛低表达，在海马体和常驻神经前体细胞中并不特别突出。由近端启动子驱动的Runx1的亚型1和2（而非3至5）在体外海马前体细胞中表达，尽管表达水平依然很低，并且在用TGF-β1刺激后显著增加。在分化条件下（去除生长因子），Runx1表达下调。体外过表达Runx1可减少增殖，通过减少细胞凋亡增加前体细胞存活，并增加神经元分化，同时略微降低树突形态和复杂性。体外在海马前体细胞中转染显性负性Runx1并未导致神经发生出现差异。在BXD重组小鼠品系中，Runx1的海马体表达与成体神经发生（前体细胞增殖）相关，并且与富集在GO类别“神经前体细胞增殖”和“神经元分化”中的共变转录本相关。因此，Runx1是参与调控成体神经发生初始分化相关步骤的一个合理候选基因。然而，Runx1对这种效应的相对贡献似乎是互补性的，并且只能解释细胞自主促分化效应的一小部分。
