Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.
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DOI:
10.1038/mp.2017.238
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发表时间:
2018-08
影响因子:
11
通讯作者:
Weiss LA
Weiss LA
中科院分区:
医学1区
文献类型:
--
作者:
Yeh E;Dao DQ;Wu ZY;Kandalam SM;Camacho FM;Tom C;Zhang W;Krencik R;Rauen KA;Ullian EM;Weiss LA

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Ras/MAPK信号通路是神经发育的主要参与者,有证据表明BRAF是Ras信号的关键介质,影响人类行为。我们研究了突变BRAFQ257R在诱导多能干细胞(iPSC)衍生的人类神经发育模型中的作用,BRAFQ257R是心表皮综合征(CFC)最常见的原因。在来自CFC受试者的ipsc衍生的神经元培养物中,我们观察到与对照组相比,p-AKT和p-ERK1/2降低,神经祖细胞池枯竭,神经元成熟迅速。药理操作PI3K/AKT通路在对照细胞中重现细胞表型,在CFC细胞中减弱细胞表型。CFC培养表现出细胞亚型比例的改变和内在兴奋性的增加。此外,在CFC细胞中,Ras/MAPK通路激活和形态异常表现出细胞亚型特异性差异。我们的结果强调了探索特定细胞亚型和使用iPSC模型揭示相关人类特异性神经发育事件的重要性。
Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.
DOI: 10.1038/ng.2711
发表时间: 2013-09
期刊: NATURE GENETICS
影响因子: 30.8
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发表时间: 2004-06-01
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影响因子: 4.8
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发表时间: 2009-02-01
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