Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

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

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
24MB
[thumbnail of Supporting Information] Other (Supporting Information)
5MB

Item Type:Article
Title:Single-cell, whole-embryo phenotyping of mammalian developmental disorders
Creators Name: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. and Spielmann, M.
Abstract:Mouse models are a critical tool for studying human diseases, particularly developmental disorders. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse. 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 sequencing 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 regions. 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.
Keywords:Cell Nucleus, Developmental Disabilities, Mammalian Embryo, Animals, Mice, Mammals
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group
Volume:623
Number:7988
Page Range:772-781
Date:23 November 2023
Official Publication:https://doi.org/10.1038/s41586-023-06548-w
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library