A survey of the mouse hindbrain in the fed and fasted state using single-nucleus RNA sequencing
A survey of the mouse hindbrain in the fed and fasted state using single-nucleus RNA sequencing
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使用单核 RNA 测序对进食和禁食状态下的小鼠后脑进行调查
DOI：
10.1101/2021.03.11.434948
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Dowsett G
中科院分区：
文献类型：
--
作者：
Dowsett G
目的位于后脑的后区（AP）和孤束核（NTS）是感知和整合外周营养信号从而调节摄食行为的关键核团。虽然单细胞转录组学已在小鼠中用于揭示关键下丘脑群体的基因表达谱和异质性，但尚未在后脑中进行类似的深入研究。方法使用单核 RNA 测序，我们对进食和禁食状态下的小鼠 AP 和 NTS 内的 16,034 个细胞进行了详细调查。结果其中，8,910 个神经元分为 30 个簇，其中 4,289 个是神经元来自禁食过夜小鼠的小鼠和 4,621 只小鼠。总共 7,124 个细胞核来自非神经元细胞，包括少突胶质细胞、星形胶质细胞和小胶质细胞。有趣的是，我们发现少突胶质细胞群在转录上对过夜禁食特别敏感。分别与 GLP1、GIP、GDF15 和胰淀素结合的受体 GLP1R、GIPR、GFRAL 和 CALCR 均在后脑中表达，是抗肥胖治疗的主要靶点。我们对这四个群体的转录组进行了表征，并表明他们的基因表达谱不会因过夜禁食而发生显着改变。值得注意的是，我们发现大约一半表达 GIPR 的细胞是少突胶质细胞。此外，我们对后脑内表达 POMC 的神经元进行了分析，并证明 84% 的 POMC 神经元表达 PCSK1、PSCK2 或两者，这意味着黑皮质素肽可能是由这些神经元产生的。结论我们提供了表达关键抗肥胖药物受体的 AP 和 NTS 细胞的详细单细胞水平特征，这些药物要么已批准用于人类使用，要么处于临床试验中。该资源将有助于描述这些化合物有效性的机制，并且在继续寻找其他新的治疗靶点方面也证明是有用的。
ObjectiveThe area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and consequently regulate feeding behaviour. While single-cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain.MethodsUsing single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of mice in the fed and fasted states.ResultsOf these, 8,910 were neurons that group into 30 clusters, with 4,289 from mice fedad libitumand 4,621 from overnight fasted mice. A total of 7,124 nuclei were from non-neuronal cells, including oligodendrocytes, astrocytes, and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL, and CALCR, which bind GLP1, GIP, GDF15, and amylin, respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC-expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2, or both, implying that melanocortin peptides are likely produced by these neurons.ConclusionWe provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds and also prove useful in the continued search for other novel therapeutic targets.
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