Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS Genet. 2022 Jun 8;18(6):e1010221. doi: 10.1371/journal.pgen.1010221. eCollection 2022 Jun.
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.
尽管人们对脆性 X 综合征 (FXS) 的病理生理学有了更多的了解，但它的分子基础仍知之甚少。全脑组织表达谱的研究结果令人惊讶地缺乏信息，因此我们应用单细胞 RNA 测序对 FMRP 缺陷型小鼠模型进行了更高分辨率的分析。我们发现，FMRP 的缺失导致高度细胞类型特异性的基因表达变化，在特定神经元类型中最为明显，其中 FMRP 结合的 mRNA 明显下调。包括翻译和呼吸作用在内的代谢途径在大多数细胞类型中显著上调，兴奋性神经元除外。这些影响表明 mTOR 途径的活性可能存在差异，再加上其他失调的途径，提示 Fmr1 敲除皮层中兴奋性神经元与抑制性神经元之间存在失衡，并且这种失衡会被星形胶质细胞加剧。我们的数据表明，FMRP 的缺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了资源。
