Single-cell spatial transcriptomic analysis reveals common and divergent features of developing postnatal granule cerebellar cells and medulloblastoma.
Single-cell spatial transcriptomic analysis reveals common and divergent features of developing postnatal granule cerebellar cells and medulloblastoma.
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DOI：
10.1186/s12915-021-01071-8
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发表时间：
2021-07-01
期刊：
影响因子：
5.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Luo W;Lin GN;Song W;Zhang Y;Lai H;Zhang M;Miao J;Cheng X;Wang Y;Li W;Wei W;Gao WQ;Yang R;Wang J
小脑神经发生涉及小脑发育过程中大量小脑颗粒神经元（GNs）的产生，这一过程涉及颗粒神经元祖细胞（GNPs）增殖和分化的严格调控。许多转录调节因子，包括Math1，以及信号分子Wnt和Shh，已被证明在GNP增殖和分化中起重要作用，而颗粒细胞发育的失调已被报道与成神经管细胞瘤的发病机制有关。虽然小脑颗粒细胞的祖细胞/分化状态已被广泛研究，但更详细的发育分化程序和空间基因表达模式之间的关联，以及它们如何导致不同类型的成神经管细胞瘤的差异产生，仍然知之甚少。在这里，我们提供了一个比较的单细胞空间转录组学分析，以更好地了解发展中的颗粒细胞和成神经管细胞瘤细胞之间的异同。为了更好地了解发育中的小脑颗粒细胞的精确细胞状态，我们对来自颗粒神经元特异性报告小鼠（Math1-GFP； Dcx-DsRed小鼠）的24,919个小鼠小脑细胞进行了单细胞RNA测序。我们的单细胞分析显示，小脑颗粒细胞的发育有四种主要状态，包括两个亚群的颗粒祖细胞和两个亚群的分化/分化颗粒神经元。进一步的空间转录组学技术使其在小脑中的空间位置可视化成为可能。此外，我们对来自patch +/−突变小鼠的18372个细胞进行了单细胞RNA测序，发现髓母细胞瘤中转化的颗粒细胞与不同分化状态的发育中的颗粒神经元非常相似。然而，髓母细胞瘤中转化颗粒神经元祖细胞的分化倾向明显低于正常发育的细胞。总之，我们的研究揭示了小脑颗粒细胞详细状态的细胞和空间组织，为正常小脑发育与肿瘤发生之间的异同提供了直接证据。在线版本包含补充材料，可在10.1186/s12915-021-01071-8获得。
Cerebellar neurogenesis involves the generation of large numbers of cerebellar granule neurons (GNs) throughout development of the cerebellum, a process that involves tight regulation of proliferation and differentiation of granule neuron progenitors (GNPs). A number of transcriptional regulators, including Math1, and the signaling molecules Wnt and Shh have been shown to have important roles in GNP proliferation and differentiation, and deregulation of granule cell development has been reported to be associated with the pathogenesis of medulloblastoma. While the progenitor/differentiation states of cerebellar granule cells have been broadly investigated, a more detailed association between developmental differentiation programs and spatial gene expression patterns, and how these lead to differential generation of distinct types of medulloblastoma remains poorly understood. Here, we provide a comparative single-cell spatial transcriptomics analysis to better understand the similarities and differences between developing granule and medulloblastoma cells. To acquire an enhanced understanding of the precise cellular states of developing cerebellar granule cells, we performed single-cell RNA sequencing of 24,919 murine cerebellar cells from granule neuron-specific reporter mice (Math1-GFP; Dcx-DsRed mice). Our single-cell analysis revealed that there are four major states of developing cerebellar granule cells, including two subsets of granule progenitors and two subsets of differentiating/differentiated granule neurons. Further spatial transcriptomics technology enabled visualization of their spatial locations in cerebellum. In addition, we performed single-cell RNA sequencing of 18,372 cells from Patched+/− mutant mice and found that the transformed granule cells in medulloblastoma closely resembled developing granule neurons of varying differentiation states. However, transformed granule neuron progenitors in medulloblastoma exhibit noticeably less tendency to differentiate compared with cells in normal development. In sum, our study revealed the cellular and spatial organization of the detailed states of cerebellar granule cells and provided direct evidence for the similarities and discrepancies between normal cerebellar development and tumorigenesis. The online version contains supplementary material available at 10.1186/s12915-021-01071-8.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
64.8
作者：
Hovestadt, Volker;Smith, Kyle S.;Northcott, Paul A.
通讯作者：
Northcott, Paul A.
影响因子：
64.8
作者：
BenArie, N;Bellen, HJ;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
64.5
作者：
Asp, Michaela;Giacomello, Stefania;Lundeberg, Joakim
通讯作者：
Lundeberg, Joakim
髓母细胞瘤的分子分类。
影响因子：
1.9
作者：
Kijima N;Kanemura Y
通讯作者：
Kanemura Y