Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Neural Dev. 2013 Jul 29;8:14. doi: 10.1186/1749-8104-8-14.
During cerebral cortex development, multipotent neural progenitor cells generate a variety of neuronal subtypes in a fixed temporal order. How a single neural progenitor cell generates the diversity of cortical projection neurons in a temporal sequence is not well understood. Based on their function in developmental timing in other systems, Dicer and microRNAs are potential candidate regulators of cellular pathways that control lineage progression in neural systems.
Cortex-specific deletion of Dicer results in a marked reduction in the cellular complexity of the cortex, due to a pronounced narrowing in the range of neuronal types generated by Dicer-null cortical stem and progenitor cells. Instead of generating different classes of lamina-specific neurons in order over the 6-day period of neurogenesis, Dicer null cortical stem and progenitor cells continually produce one class of deep layer projection neuron. However, gliogenesis in the Dicer-null cerebral cortex was not delayed, despite the loss of multipotency and the failure of neuronal lineage progression.
We conclude that Dicer is required for regulating cortical stem cell multipotency with respect to neuronal diversity, without affecting the larger scale switch from neurogenesis to gliogenesis. The differences in phenotypes reported from different timings of Dicer deletion indicate that the molecular pathways regulating developmental transitions are notably dosage sensitive.
在大脑皮层发育过程中，多能神经祖细胞以固定的时间顺序产生多种神经元亚型。单个神经祖细胞如何按照时间顺序产生皮质投射神经元的多样性还不是很清楚。基于其在其他系统发育时间中的功能，Dicer 和 microRNAs 是控制神经系统谱系进展的细胞途径的潜在候选调节剂。
皮层特异性 Dicer 缺失导致皮层的细胞复杂性明显降低，这是由于 Dicer 缺失的皮层干细胞和祖细胞产生的神经元类型范围明显变窄。Dicer 缺失的皮层干细胞和祖细胞没有按照神经发生的 6 天周期顺序产生不同类别的层特异性神经元，而是持续产生一类深层投射神经元。然而，Dicer 缺失大脑皮层的神经胶质发生并没有延迟，尽管多能性丧失和神经元谱系进展失败。
我们得出结论，Dicer 是调节皮层干细胞多能性与神经元多样性所必需的，而不影响从神经发生到神经胶质发生的更大规模转变。不同时间点 Dicer 缺失所报告的表型差异表明，调节发育转变的分子途径对剂量非常敏感。
