Single cell transcriptomics reveals dysregulated cellular and molecular networks in a fragile X syndrome model.
Single cell transcriptomics reveals dysregulated cellular and molecular networks in a fragile X syndrome model.
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DOI：
10.1371/journal.pgen.1010221
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发表时间：
2022-06
期刊：
影响因子：
4.5
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中科院分区：
文献类型：
--
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尽管对脆性 X 综合征 (FXS) 的病理生理学的了解取得了进展，但其分子基础仍然知之甚少。事实证明，全脑组织表达谱的信息量令人惊讶，因此我们应用单细胞 RNA 测序以更高分辨率来分析 FMRP 缺陷小鼠模型。我们发现，FMRP 的缺失会导致高度细胞类型特异性的基因表达变化，这种变化在特定神经元类型中最为强烈，其中 FMRP 结合的 mRNA 显着下调。大多数细胞类型的代谢途径（包括翻译和呼吸）均显着上调，但兴奋性神经元除外。这些效应表明 mTOR 通路活性的潜在差异，并与其他失调通路一起表明 Fmr1 敲除皮质中的兴奋性抑制不平衡，而星形胶质细胞会加剧这种不平衡。我们的数据表明，FMRP 丢失会影响关键细胞通讯基因的丰度，这些基因可能会影响神经元突触，并为探究这种疾病的生物学基础提供资源。脆性 X 综合征是遗传性智力障碍和自闭症谱系障碍的主要原因。它是由单个基因 FMR1 失活以及其编码蛋白 FMRP 丢失引起的。尽管进行了数十年的深入研究，我们仍然缺乏对该疾病的分子和生物学后果的概述。使用单细胞 RNA 测序，我们对健康小鼠和缺乏 FMRP 蛋白（这种疾病的常见模型）的基因敲除小鼠的大脑细胞进行了分析，以识别不同细胞类型之间发生的分子变化。我们发现神经元是受影响最大的细胞类型，其中多个途径中的基因也受到类似的影响。这包括已知与 FMRP 结合的转录本，这些转录本仅在神经元中集体减少，而在其他细胞类型中则不会减少。我们的结果表明 FMRP 的缺失如何影响不同脑细胞类型之间复杂的相互作用，这可以为治疗干预措施的发展提供新的视角。
Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular basis is still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative, therefore we applied single cell RNA sequencing to profile an FMRP deficient mouse model with higher resolution. We found that the absence of FMRP results in highly cell type specific gene expression changes that are strongest among specific neuronal types, where FMRP-bound mRNAs were prominently downregulated. Metabolic pathways including translation and respiration are significantly upregulated across most cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways, suggest an excitatory-inhibitory imbalance in the Fmr1-knock out cortex that is exacerbated by astrocytes. Our data demonstrate that FMRP loss affects abundance of key cellular communication genes that potentially affect neuronal synapses and provide a resource for interrogating the biological basis of this disorder. Fragile X syndrome is a leading genetic cause of inherited intellectual disability and autism spectrum disorder. It results from the inactivation of a single gene, FMR1 and hence the loss of its encoded protein FMRP. Despite decades of intensive research, we still lack an overview of the molecular and biological consequences of the disease. Using single cell RNA sequencing, we profiled cells from the brain of healthy mice and of knock-out mice lacking the FMRP protein, a common model for this disease, to identify molecular changes that happen across different cell types. We find neurons are the most impacted cell type, where genes in multiple pathways are similarly impacted. This includes transcripts known to be bound by FMRP, which are collectively decreased only in neurons but not in other cell types. Our results show how the loss of FMRP affects the intricate interactions between different brain cell types, which could provide new perspectives to the development of therapeutic interventions.
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