Harris Lachlan, Zalucki Oressia, Clément Olivier, Fraser James, Matuzelski Elise, Oishi Sabrina, Harvey Tracey J, Burne Thomas H J, Heng Julian Ik-Tsen, Gronostajski Richard M, Piper Michael
The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia 4072.
Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia 6102.
Development. 2018 Feb 7;145(3):dev155689. doi: 10.1242/dev.155689.
Our understanding of the transcriptional programme underpinning adult hippocampal neurogenesis is incomplete. In mice, under basal conditions, adult hippocampal neural stem cells (AH-NSCs) generate neurons and astrocytes, but not oligodendrocytes. The factors limiting oligodendrocyte production, however, remain unclear. Here, we reveal that the transcription factor NFIX plays a key role in this process. NFIX is expressed by AH-NSCs, and its expression is sharply upregulated in adult hippocampal neuroblasts. Conditional ablation of from AH-NSCs, coupled with lineage tracing, transcriptomic sequencing and behavioural studies collectively reveal that NFIX is cell-autonomously required for neuroblast maturation and survival. Moreover, a small number of AH-NSCs also develop into oligodendrocytes following deletion. Remarkably, when is deleted specifically from intermediate progenitor cells and neuroblasts using a - driver, these cells also display elevated signatures of oligodendrocyte gene expression. Together, these results demonstrate the central role played by NFIX in neuroblasts within the adult hippocampal stem cell neurogenic niche in promoting the maturation and survival of these cells, while concomitantly repressing oligodendrocyte gene expression signatures.
我们对支撑成年海马体神经发生的转录程序的理解并不完整。在小鼠中，在基础条件下，成年海马体神经干细胞（AH-NSCs）产生神经元和星形胶质细胞，但不产生少突胶质细胞。然而，限制少突胶质细胞产生的因素仍不清楚。在这里，我们揭示转录因子NFIX在这一过程中起关键作用。NFIX由AH-NSCs表达，其表达在成年海马体神经母细胞中急剧上调。从AH-NSCs中条件性敲除NFIX，并结合谱系追踪、转录组测序和行为研究共同表明，NFIX是神经母细胞成熟和存活所必需的细胞自主因子。此外，少数AH-NSCs在NFIX缺失后也发育成少突胶质细胞。值得注意的是，当使用一个Cre驱动子从中间祖细胞和神经母细胞中特异性敲除NFIX时，这些细胞也显示出少突胶质细胞基因表达的增强特征。这些结果共同证明了NFIX在成年海马体干细胞神经发生微环境中的神经母细胞中所起的核心作用，即促进这些细胞的成熟和存活，同时抑制少突胶质细胞基因表达特征。
