Oxysterol-liver X receptor signaling mediates CYFIP1 regulation of cortical neurogenesis
Oxysterol-liver X receptor signaling mediates CYFIP1 regulation of cortical neurogenesis
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DOI：
10.1101/2023.06.23.546272
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发表时间：
2023-06
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影响因子：
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通讯作者：
D. C. De La Fuente;C. Tamburini;Emily Stonelake;W. Griffiths;J. Hall;M. Owen;D. Linden;A. Pocklington;Yuqin Wang;Meng-Yen Li
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作者：
D. C. De La Fuente;C. Tamburini;Emily Stonelake;W. Griffiths;J. Hall;M. Owen;D. Linden;A. Pocklington;Yuqin Wang;Meng-Yen Li
神经前体细胞增殖和神经元分化的失调已被越来越多地认为是神经细胞中的一种常见病理，具有神经精神和神经发育障碍的遗传风险，但其潜在的分子机制在很大程度上仍不清楚。含有CYFIP1基因的15q11.2区域的缺失和重复与自闭症和精神分裂症有关。使用携带15q11.2缺失的患者来源的IPSCs和具有CYFIP1功能获得和丧失的遗传操作的hESCs(GoF和LoF)，我们发现15q11.2缺失和CYFIP1-LoF导致神经元提前分化，而CYFIP1-GoF有利于神经前体细胞的维持。我们发现，胆固醇的生物合成和代谢是一个生物过程，受到CYFIP1剂量变化的干扰，导致神经氧固醇谱的改变。24S，25-环氧胆固醇在CYFIP1-GOF中降低，在15q11.2del和15q11.2del神经细胞中升高，可以通过促进皮质神经元分化来模拟15q11.2del和CYFIP1-LoF的表型，恢复受损的神经前体细胞分化。此外，脑中表达的肝X受体LXRb亚型的基因缺失后，24S，25-环氧胆固醇的神经发生活性丧失，而在CYFIP1-/-背景中表达的LXRb的复合缺失挽救了他们过早的神经发生。在携带15q11.2CNV的神经细胞中，LXR介导的氧化甾醇调节神经发生是一种新的病理机制，并为与该危险基因相关的遗传性疾病的治疗策略提供了潜在的靶点。
Dysregulation in neural progenitor proliferation and neuronal differentiation has been increasingly recognised as a common pathology in neural cells harboring genetic risks to neuropsychiatric and neurodevelopmental disorders, yet the underlying molecular mechanisms remains largely unknown. Deletions and duplications of the 15q11.2 region containing the CYFIP1 gene have been associated with autism and schizophrenia. Using patient-derived iPSCs carrying 15q11.2 deletion and genetically manipulated hESCs with CYFIP1 gain- and loss-of-function (GoF and LoF), we show that 15q11.2 deletion and CYFIP1-LoF leads to premature neuronal differentiation while CYFIP1-GoF favours neural progenitor maintenance. We identified cholesterol biosynthesis and metabolism as a biological process disturbed by CYFIP1 dosage change, leading to altered neuro-oxysterol profiles. 24S,25-epoxycholesterol, which was decreased in CYFIP1-GoF and increased in CYFIP1-LoF and 15q11.2del neural cells, can mimic the 15q11.2del and CYFIP1-LoF phenotype by promoting cortical neuronal differentiation and restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of the brain expressed isoform of the liver X receptor LXRb while compound deletion of LXRb in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR mediated oxysterol regulation of neurogenesis as a novel pathological mechanism in neural cells carrying 15q11.2CNV and provides a potential target for therapeutic strategies for genetic disorders associated with this risk locus.