Global S&T Development Trend Analysis Platform of Resources and Environment
| DOI | 10.1126/science.abf5759 |
| The coding and long noncoding single-cell atlas of the developing human fetal striatum | |
| Vittoria Dickinson Bocchi; Paola Conforti; Elena Vezzoli; Dario Besusso; Claudio Cappadona; Tiziana Lischetti; Maura Galimberti; Valeria Ranzani; Raoul J. P. Bonnal; Marco De Simone; Grazisa Rossetti; Xiaoling He; Kenji Kamimoto; Ira Espuny-Camacho; Andrea Faedo; Federica Gervasoni; Romina Vuono; Samantha A. Morris; Jian Chen; Dan Felsenfeld; Giulio Pavesi; Roger A. Barker; Massimiliano Pagani; Elena Cattaneo | |
| 2021-05-07 | |
| 发表期刊 | Science
 |
| 出版年 | 2021 |
| 英文摘要 | Deep in the brain, the striatum receives and coordinates inputs from other parts of the brain. Bocchi et al. surveyed molecular features as the striatum develops in the human brain. Single-cell surveys of long intergenic noncoding RNAs revealed a progenitor for medium spiny neurons and provide insight into evolutionary divergence of this critical part of the brain. Science , this issue p. [eabf5759][1] ### INTRODUCTION The striatum modulates distinct characteristics of human social behavior and is an area affected in many neurological diseases. We created a comprehensive single-cell atlas of this area during early human fetal development, considering both protein-coding transcripts and long intergenic noncoding RNAs (lincRNAs). ### RATIONALE Understanding of the molecular mechanisms that define human striatal development has been limited by the scarcity of relevant fetal tissue and the use of only a limited panel of protein-coding genes in most gene identification studies. We created a cell-specific molecular atlas of the lateral ganglionic eminence (LGE), the striatal primordium. Our first goal was to develop a catalog of de novo identified lincRNAs of this area using bulk RNA sequencing. This catalog should help to clarify the specific characteristics of human development because lincRNAs exhibit accelerated evolution, are highly cell-specific, and are required for brain development. Our second goal was to understand how the medium spiny neurons (MSNs), the principal cell types in the striatum, differentiate and diversify, and which genes act as master regulators of fate determination. MSNs diversify into D1 and D2 types, so named for their expression of one of the two variants of the human dopamine receptor (D1 and D2). We used single-cell RNA sequencing to infer the developmental landscape of MSNs and to define and validate fate markers. ### RESULTS Bulk RNA sequencing enabled the annotation of 1116 novel lincRNAs of different areas of the human developing telencephalon, and we found that these lincRNAs are less conserved among species than those previously identified in the adult brain. Bulk measurements enabled us to pinpoint the distinctive signature of the striatum relative to surrounding areas, and we determined that huntingtin (HTT) is a specific upstream regulator of this region. We then profiled 96,789 single cells of the LGE, based on both coding RNAs and the newly identified lincRNAs. This enabled us to uncover the transcriptional profiles of 15 different cell states that included lincRNAs that were gained throughout evolution. We found that a common progenitor generates both D1- and D2-MSNs and that this progenitor is distinct from the progenitor of interneurons. We also discovered a postmitotic precursor cell state for both D1- and D2-MSNs, which falls within a continuum of key fate determinants. Finally, we identified a panel of gene regulatory networks that define D1- and D2-MSNs, and we showed that in silico knockout of the transcription factors governing these networks could cause the arrest of both MSN lineages, blockage of a specific MSN class, or switching between MSN fates. ### CONCLUSION Our findings reveal the differentiation hierarchies that govern human striatal development. We anticipate that the set of transcription factors and lincRNAs identified in this study will be leveraged to recreate MSN differentiation in vitro and that these cells can then be used for cell replacement therapies in Huntington’s disease (HD). Furthermore, we expect that this atlas will guide investigations of the developmental components related to HD. Finally, we foresee that our lincRNA catalog will contribute to understanding the additional layer of fine-tuning mechanisms present in the human striatum but not in other species. ![Figure][2] The molecular blueprint of striatal development. Combined bulk and single-cell RNA sequencing of the human fetal striatum reveals cell states together with their key coding and lincRNA fate determinants, and defines the developmental hierarchies underlying lineage commitment in medium spiny neurons. CX, neocortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence. ILLUSTRATION: TIZIANA LISCHETTI Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type–specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment. [1]: /lookup/doi/10.1126/science.abf5759 [2]: pending:yes |
| 领域 | 气候变化 ; 资源环境 |
| URL | 查看原文 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/325933 |
| 专题 | 气候变化 资源环境科学 |
| 推荐引用方式 GB/T 7714 | Vittoria Dickinson Bocchi,Paola Conforti,Elena Vezzoli,et al. The coding and long noncoding single-cell atlas of the developing human fetal striatum[J]. Science,2021. |
| APA | Vittoria Dickinson Bocchi.,Paola Conforti.,Elena Vezzoli.,Dario Besusso.,Claudio Cappadona.,...&Elena Cattaneo.(2021).The coding and long noncoding single-cell atlas of the developing human fetal striatum.Science. |
| MLA | Vittoria Dickinson Bocchi,et al."The coding and long noncoding single-cell atlas of the developing human fetal striatum".Science (2021). |
| 条目包含的文件 | 条目无相关文件。 | |||||
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。
修改评论