Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders.
Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders.
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DOI：
10.1038/s41593-022-01150-1
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发表时间：
2022-09
影响因子：
25
通讯作者：
Allen, Nicola J.
中科院分区：
文献类型：
--
作者：
Caldwell, Alison L. M.;Sancho, Laura;Deng, James;Bosworth, Alexandra;Miglietta, Audrey;Diedrich, Jolene K.;Shokhirev, Maxim N.;Allen, Nicola J.
星形胶质细胞在许多神经发育障碍（NDs）模型中对神经元发育产生负面影响，然而它们是如何做到这一点的，以及它们在各种疾病中是否有共同的机制，目前尚不清楚。在这里，我们开发了一种细胞培养系统，以了解三种遗传性NDs （Rett，脆性X和唐氏综合征）小鼠模型中星形胶质细胞蛋白分泌和基因表达的变化。ND星形胶质细胞增加Igfbp2的释放，IGF的分泌抑制剂。IGF可以缓解许多nd中的神经元缺陷，我们发现阻断Igfbp2可以部分缓解Rett综合征星形胶质细胞的抑制作用，这表明星形胶质细胞Igfbp2的增加有助于nd中IGF信号的减少。我们发现BMP信号的增加是蛋白分泌变化的上游，包括Igfbp2，在脆性X和Rett综合征星形胶质细胞中阻断BMP信号逆转了对神经突生长的抑制作用。这项工作提供了健康和ND模型中星形胶质细胞分泌蛋白的资源，并确定了不同ND干预的新靶点。
Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs), however how they do this, and if mechanisms are shared across disorders, is not known. Here, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down Syndromes). ND astrocytes increase release of Igfbp2, a secreted inhibitor of IGF. IGF rescues neuronal deficits in many NDs, and we found blocking Igfbp2 partially rescues inhibitory effects of Rett Syndrome astrocytes, suggesting increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett Syndrome astrocytes reverses inhibitory effects on neurite outgrowth. This work provides a resource of astrocyte secreted proteins in health and ND models, and identifies novel targets for intervention in diverse NDs.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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来自小鼠大脑多个区域的老化星形胶质细胞转录组。
影响因子：
8.8
作者：
Boisvert MM;Erikson GA;Shokhirev MN;Allen NJ
通讯作者：
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