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 BRAF^Q257R, 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.

中文翻译：

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患者来源的 iPSC 显示出过早的神经分化和与神经发育相关的神经元类型特异性表型。


Ras/MAPK 通路信号传导是神经发育的主要参与者，有证据表明 BRAF 作为关键的 Ras 信号介质，影响人类行为。我们研究了 BRAF ^Q257R突变（心面皮肤综合征 (CFC) 的最常见原因）在诱导多能干细胞 (iPSC) 衍生的人类神经发育模型中的作用。在来自 CFC 受试者的 iPSC 衍生神经元培养物中，我们观察到与对照组相比，p-AKT 和 p-ERK1/2 减少，以及神经祖细胞库耗尽和神经元快速成熟。药理学 PI3K/AKT 通路操作重现了对照细胞中的细胞表型，并在 CFC 细胞中减弱了它们。 CFC 培养物显示出细胞亚型比率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。