Foxg1 Overexpression in Neocortical Pyramids Stimulates Dendrite Elongation Via Hes1 and pCreb1 Upregulation
Foxg1 Overexpression in Neocortical Pyramids Stimulates Dendrite Elongation Via Hes1 and pCreb1 Upregulation
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DOI：
10.1093/cercor/bhy007
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发表时间：
2019-03-01
期刊：
影响因子：
3.7
通讯作者：
Mallamaci, Antonello
中科院分区：
文献类型：
--
作者：
Chiola, Simone;Mihn Duc Do;Mallamaci, Antonello
新皮质投射神经元的结构受到复杂的基因控制。在这里，我们证明了 Foxg1（一种转录因子基因，它塑造了早期大脑的模式并设定了端脑神经元发生的速度），专门刺激树突伸长。这种现象在体内发生，就像在体外一样，甚至在 Foxg1 表达水平发生适度变化时也可以检测到。我们发现 Foxg1 通过刺激 Hes1 发挥作用，Hes1 进而上调 pCreb1（一种著名的促树突生成效应子），并下调 Syt 和 Ndr1（两种已确定的树突伸长拮抗剂）。此外，Foxg1 驱动的 pCreb1 上调需要 PKA 和 AKT，并与 PP1 和 PP2A 磷酸酶活性降低相关。这些发现有助于阐明神经突发生的正常神经发育和活动相关调节。他们进一步表明，FOXG1 等位基因剂量异常的 West 和 Rett 综合征患者中可能会出现新皮质投射神经元树突树大小异常，并导致其神经病理学特征。
The architecture of neocortical projection neurons is subject of a complex gene control. Here we demonstrated that Foxg1, a transcription factor gene which patterns the early rostral brain and sets the pace of telencephalic neuronogenesis, specifically stimulates dendrite elongation. This phenomenon occurs in vivo like in vitro, and it is detectable even upon moderate changes of Foxg1 expression levels. We found that Foxg1 acts by stimulating Hes1, which in turn upregulates pCreb1, a well-known pro-dendritogenic effector, and downregulates Syt and Ndr1, namely two established antagonizers of dendrite elongation. Moreover, Foxg1-driven pCreb1 upregulation requires PKA and AKT, and correlates with reduced PP1 and PP2A phosphatase activity. These findings contribute to clarify normal neurodevelopmental and activity-related regulation of neuritogenesis. They further suggest that an abnormal sizing of the dendritic tree of neocortical projection neurons may occur in West and Rett syndrome patients with anomalous FOXG1 allele dosages and contribute to their neurolopathological profiles.