Foxg1 Antagonizes Neocortical Stem Cell Progression to Astrogenesis
Foxg1 Antagonizes Neocortical Stem Cell Progression to Astrogenesis
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DOI：
10.1093/cercor/bhz031
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发表时间：
2019-12-01
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：
Falcone, Carmen;Santo, Manuela;Mallamaci, Antonello
新皮质星形细胞发生在神经元发生之后，先于寡聚细胞发生。在决定其时间清晰度的关键因素中，有皮质干细胞(SCs)向星形胶质细胞谱系的进行率，以及星形胶质细胞分化程序对外部胶质形成信号的反应的激活率。在这项研究中，我们发现FOXG1SC的高表达抑制了星形胶质细胞的生成，同时刺激了SC的自我更新，并将SCs转化为神经元发生。我们发现，这种活性的机制主要是细胞自主性和高度多效性。它们包括协调下调4个关键效应因子，将神经干细胞引导到星形胶质细胞的命运，以及执行星形胶质细胞分化计划的核心分子机制的激活缺陷。接下来，我们发现SC FOXG1的水平在神经发生向神经胶质形成的转变过程中特异性地下降，这表明FOXG1在星形细胞发生的时间调控中发挥了关键作用。最后，我们发现FOXG1抑制了人类新皮质前体的星形发生，这表明这是一个进化上古老的特征。
Neocortical astrogenesis follows neuronogenesis and precedes oligogenesis. Among key factors dictating its temporal articulation, there are progression rates of pallial stem cells (SCs) towards astroglial lineages as well as activation rates of astrocyte differentiation programs in response to extrinsic gliogenic cues. In this study, we showed that high Foxg1 SC expression antagonizes astrocyte generation, while stimulating SC self-renewal and committing SCs to neuronogenesis. We found that mechanisms underlying this activity are mainly cell autonomous and highly pleiotropic. They include a concerted downregulation of 4 key effectors channeling neural SCs to astroglial fates, as well as defective activation of core molecular machineries implementing astroglial differentiation programs. Next, we found that SC Foxg1 levels specifically decline during the neuronogenic-to-gliogenic transition, pointing to a pivotal Foxg1 role in temporal modulation of astrogenesis. Finally, we showed that Foxg1 inhibits astrogenesis from human neocortical precursors, suggesting that this is an evolutionarily ancient trait.