Modification of Pax6 and Olig2 Expression in Adult Hippocampal Neurogenesis Selectively Induces Stem Cell Fate and Alters Both Neuronal and Glial Populations
Modification of Pax6 and Olig2 Expression in Adult Hippocampal Neurogenesis Selectively Induces Stem Cell Fate and Alters Both Neuronal and Glial Populations
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DOI：
10.1002/stem.1005
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发表时间：
2012-03-01
期刊：
影响因子：
5.2
通讯作者：
Peterson, Daniel A.
中科院分区：
文献类型：
--
作者：
Klempin, Friederike;Marr, Robert A.;Peterson, Daniel A.
哺乳动物海马中新神经元的产生在整个生命过程中持续进行，并且谱系进展受转录因子、局部线索和环境影响的调节。原位指导干/祖细胞命运的能力可能具有治疗潜力。使用体内逆转录病毒的交付和谱系追踪的方法，我们比较了谱系指令因子，Pax 6和Olig 2，并证明两者都参与成年大鼠成年海马神经发生的调节。我们发现，过度表达的前神经元因子Pax 6推动神经元前体细胞的早期成熟，并增加神经元表型的频率。然而，Pax 6过表达在3周时没有导致神经发生的净增加。阻断Olig 2功能会减少和减缓神经元的定型和分化，并减少净神经发生。改变这两种因子的表达也会改变胶质细胞的生成。我们的研究结果表明，Pax 6减少神经胶质细胞2祖细胞的数量，并防止少突胶质细胞谱系的承诺，而Olig 2的抑制导致扩大星形胶质细胞谱系。我们的结论是，选择性地修改海马祖细胞内的转录线索是足以诱导细胞的命运开关，从而改变神经发生胶质细胞比例。此外，我们的数据显示了多个祖细胞谱系对同一信号的不同反应的能力。因此，指导指导性线索选择表型和发育阶段可能是至关重要的，以实现精确的结果，在细胞发生。进一步了解靶区域内所有祖细胞群体中谱系进展的调节对于开发指导脑修复细胞命运的治疗策略将是重要的。干细胞2012;30：500-509
The generation of new neurons in the mammalian hippocampus continues throughout life, and lineage progression is regulated by transcription factors, local cues, and environmental influences. The ability to direct stem/progenitor cell fate in situ may have therapeutic potential. Using an in vivo retroviral delivery and lineage tracing approach, we compare the lineage-instruction factors, Pax6 and Olig2, and demonstrate that both participate in regulation of adult hippocampal neurogenesis in adult rats. We show that overexpression of the proneuronal factor Pax6 pushes neuronal precursor cells to early maturation and increases the frequency of neuronal phenotypes. However, Pax6 overexpression results in no net increase in neurogenesis at 3 weeks. Blocking of Olig2 function reduces and slows neuronal commitment and differentiation and decreases net neurogenesis. Altering expression of both factors also changes gliogenesis. Our results establish that Pax6 decreases the number of Neuron-Glia 2 progenitor cells and prevents oligodendrocytic lineage commitment, while repression of Olig2 results in an expanded astrocytic lineage. We conclude that selectively modifying transcriptional cues within hippocampal progenitor cells is sufficient to induce a cell fate switch, thus altering the neurogenesis-gliogenesis ratio. In addition, our data show the competence of multiple progenitor lineages to respond divergently to the same signal. Therefore, directing instructive cues to select phenotype and developmental stage could be critical to achieve precise outcomes in cell genesis. Further understanding the regulation of lineage progression in all progenitor populations within the target region will be important for developing therapeutic strategies to direct cell fate for brain repair. STEM CELLS 2012;30:500-509