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Huang, X.* ; Henck, J.* ; Qiu, C.* ; Sreenivasan, V.K.A.* ; Balachandran, S.* ; Amarie, O.V. ; Hrabě de Angelis, M. ; Behncke, R.Y.* ; Chan, W.L.* ; Despang, A.* ; Dickel, D.E.* ; Duran, M.* ; Feuchtinger, A. ; Fuchs, H. ; Gailus-Durner, V. ; Haag, N.* ; Hägerling, R.* ; Hansmeier, N.* ; Hennig, F.* ; Marshall, C.* ; Rajderkar, S.* ; Ringel, A.* ; Robson, M.* ; Saunders, L.M.* ; da Silva Buttkus, P. ; Spielmann, N. ; Srivatsan, S.R.* ; Ulferts, S.* ; Wittler, L.* ; Zhu, Y.* ; Kalscheuer, V.M.* ; Ibrahim, D.M.* ; Kurth, I.* ; Kornak, U.* ; Visel, A.* ; Pennacchio, L.A.* ; Beier, D.R.* ; Trapnell, C.* ; Cao, J.* ; Shendure, J.* ; Spielmann, M.*

Single-cell, whole-embryo phenotyping of mammalian developmental disorders.

Nature 623, 772-781 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Mesenchymal Stem-cells; Campomelic Dysplasia; Knockout Mouse; Floor Plate; Sox9; Differentiation; Expression; Platform; Gli2; Heterogeneity
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 623, Heft: 7988, Seiten: 772-781 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
CF Pathology & Tissue Analytics (CF-PTA)
Förderungen National Institutes of Health (NIH)
Alex's Lemonade Stand's Crazy 8 Initiative
Bonita and David Brewer Fellowship
US NIH grants
US Department of Energy
Deutsche Forschungsgemeinschaft (DFG)
Paul G. Allen Frontiers Foundation (Allen Discovery Center grant)
ERA-Net for Research on Rare Diseases (EUROGLYCAN-omics)
European Union (ERC, PREVENT)
Deutsches Zentrum fur Luft-und Raumfahrt
National Institute of Child Health and Human Development
NIH
Rockefeller University
German Federal Ministry of Education and Research (Infrafrontier grant)
German Center for Diabetes Research (DZD)