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Science Journals — AAAS RESEARCH ◥ was to understand how the medium spiny RESEARCH ARTICLE SUMMARY neurons (MSNs), the principal cell types in the striatum, differentiate and diversify, and which NEURODEVELOPMENT genes act as master regulators of fate determi- nation. MSNs diversify into D1 and D2 types, so The coding and long noncoding single-cell atlas named for their expression of one of the two variants of the human dopamine receptor (D1 of the developing human fetal striatum and D2). We used single-cell RNA sequencing to infer the developmental landscape of MSNs Vittoria Dickinson Bocchi, Paola Conforti, Elena Vezzoli, Dario Besusso, Claudio Cappadona, Tiziana Lischetti, and to define and validate fate markers. 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, RESULTS: Bulk RNA sequencing enabled the Jian Chen, Dan Felsenfeld, Giulio Pavesi, Roger A. Barker, Massimiliano Pagani*, Elena Cattaneo* annotation of 1116 novel lincRNAs of different areas of the human developing telencephalon, and we found that these lincRNAs are less con- INTRODUCTION: The striatum modulates dis- levant fetal tissue and the use of only a limited served among species than those previously tinct characteristics of human social behavior panel of protein-coding genes in most gene identified in the adult brain. Bulk measure- andisanareaaffectedinmanyneurological identification studies. We created a cell-specific ments enabled us to pinpoint the distinctive diseases. We created a comprehensive single- molecular atlas of the lateral ganglionic emi- signature of the striatum relative to surround- cell atlas of this area during early human fetal nence (LGE), the striatal primordium. Our first ing areas, and we determined that huntingtin development, considering both protein-coding goal was to develop a catalog of de novo iden- (HTT) is a specific upstream regulator of this Downloaded from transcripts and long intergenic noncoding tified lincRNAs of this area using bulk RNA region. We then profiled 96,789 single cells of RNAs (lincRNAs). sequencing. This catalog should help to clarify the LGE, based on both coding RNAs and the the specific characteristics of human develop- newly identified lincRNAs. This enabled us to RATIONALE: Understanding of the molecular ment because lincRNAs exhibit accelerated uncover the transcriptional profiles of 15 dif- mechanisms that define human striatal devel- evolution, are highly cell-specific, and are re- ferent cell states that included lincRNAs that opment has been limited by the scarcity of re- quired for brain development. Our second goal were gained throughout evolution. We found http://science.sciencemag.org/ 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 regula- tory networks that define D1- and D2-MSNs, Gene regulatory and we showed that in silico knockout of the networks Human-specific transcription factors governing these networks lincRNAs could cause the arrest of both MSN lineages, on July 25, 2021 blockage of a specific MSN class, or switching Driver genes between MSN fates. Medium spiny neurons CONCLUSION: Our findings reveal the differen- CX In silico gene tiation hierarchies that govern human striatal perturbation development. We anticipate that the set of LGE transcription factors and lincRNAs identified MGE in this study will be leveraged to recreate MSN differentiation in vitro and that these cells can Lineage reconstruction Progenitors 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. Validation 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.▪ Cell type discovery The list of author affiliations is available in the full article online. lincRNA *Corresponding author. Email: [email protected] (E.C.); Gene signatures identification [email protected] (M.P.) Cite this article as V. D. Bocchi et al., Science 372,eabf5759 The molecular blueprint of striatal development. Combined bulk and single-cell RNA sequencing of the (2021). DOI: 10.1126/science.abf5759 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, READ THE FULL ARTICLE AT ILLUSTRATION: TIZIANA LISCHETTI neocortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence. https://doi.org/10.1126/science.abf5759 Bocchi et al., Science 372, 591 (2021) 7 May 2021 1of1 RESEARCH ◥ conceptional weeks (pcw), with at least two RESEARCH ARTICLE or three biological replicates for each devel- opmental stage (table S1). We then profiled NEURODEVELOPMENT by RNA-seq the transcriptome of each area (Fig. 1A) and set up a computational pipeline The coding and long noncoding single-cell atlas (fig. S1A) to create a corresponding catalog of lincRNAs (fig. S1, B to E). Because our bulk of the developing human fetal striatum RNA-seq protocol was unstranded, and be- cause genic lncRNAs are difficult to correctly Vittoria Dickinson Bocchi1,2, Paola Conforti1,2, Elena Vezzoli1,2†, Dario Besusso1,2, predict without strand information discriminat- Claudio Cappadona1,2‡, Tiziana Lischetti1,2, Maura Galimberti1,2, Valeria Ranzani2, ing them from overlapping genes, we decided to Raoul J. P. Bonnal2§, Marco De Simone2¶, Grazisa Rossetti2§, Xiaoling He3, Kenji Kamimoto4,5,6, include only a reliable set of intergenic lncRNAs Ira Espuny-Camacho1,2#, Andrea Faedo1,2**, Federica Gervasoni2,7§, Romina Vuono3††, (lincRNAs). To better understand the relation- Samantha A. Morris4,5,6, Jian Chen8, Dan Felsenfeld8, Giulio Pavesi1, Roger A. Barker3, ship between lincRNAs identified in other Massimiliano Pagani2,7§*, Elena Cattaneo1,2* tissues and our newly identified lincRNAs, we integrated two catalogs derived from dif- Deciphering how the human striatum develops is necessary for understanding the diseases that affect ferent human tissues and cell types (7, 8), plus this region. To decode the transcriptional modules that regulate this structure during development, we a lincRNA catalog of the developing human compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled CX (9), into this study. 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons We detected 1116 novel lincRNA loci (Fig. 1B (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the and table S2), among which the highest num- Downloaded from postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. ber was found in the developing LGE and the We then uncovered cell type–specific gene regulatory networks that we validated through in silico lowest in the CX (fig. S1F), probably because of perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of the greater extent of data available from the this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment. CX. We found that lincRNAs had an average of 2.27 exons; this was also the case for all lincRNA catalogs integrated into this study, http://science.sciencemag.org/ he striatum, a subcortical structure made During development, MSNs are derived from with the exception of the FANTOM catalog, up of the caudate nucleus and putamen, progenitors in the lateral ganglionic eminence which used CAGE-seq instead of classic RNA- is important in motor control and learn- (LGE) of the telencephalon (4). Most studies of seq and showed fewer exons (fig. S1G). For each T ing, procedural behavior, cognition, and this area have concentrated on rodent models sampled pcw, we then defined a signature of emotional and motivational responses. and the coding signature of limited cell types. protein-coding genes and lincRNAs that were Many of these functions are associated with Long noncoding RNAs (lncRNAs) have a higher uniquely expressed in either the LGE, the CX, or uniquely human abilities including the devel- tissue specificity than mRNAs (5) and a diver- the MGE (Fig. 1C, fig. S2A, and table S3). Gene opment of speech and language (1). In adults, sity that correlates more closely with brain com- Ontology (GO) analysis in the LGE between 7 the striatum is primarily composed of medium plexity than protein-coding genes (6). LncRNAs and 11 pcw revealed an enrichment for terms spiny neurons (MSNs) carrying either D1-type may, therefore, better discriminate cell states related to neural differentiation and to forebrain or D2-type dopamine receptors interspersed during striatal development in humans. and subpallium development (fig. S2B and table on July 25, 2021 with aspiny interneurons (2). This organiza- In this study, we first conducted bulk RNA- S4), whereas at 20 pcw this changed to regula- tion does not appear to vary among species (3). seq to identify novel long intergenic noncoding tion of synaptic
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