High-resolution gene expression maps have been combined with single-cell genomics data to create a new resource for studying how cells adopt different identities during mammalian development. The Spatial Mouse Atlas is the result of a collaboration between researchers at the Babraham Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI), the Cambridge Stem Cell Institute, the Cancer Research UK (CRUK) Cambridge Institute, and the California Institute of Technology (Caltech) and colleagues.
Cell fate decisions determine how cells develop into different cell types. The development of different cell types eventually leads to the formation of all the different tissues in the body. This complex process involves many different signals from surrounding tissues, as well as mechanical constraints, epigenetic modifications and changes to gene expression. These factors create unique cell and tissue types, which eventually give rise to all major organs in a process called organogenesis.
Studies using single-cell RNA sequencing (scRNAseq) have provided insights into how the molecular landscape of cells in the mouse embryo changes during early development. However, scRNAseq methods require the cells in the embryo to be dissociated – or separated – which means spatial information is lost.
This study, published in Nature Biotechnology, combines scRNAseq data with spatially-resolved expression profiles to generate an atlas of gene expression at single-cell resolution across the entire embryo.
Visualisation of cell atlas
Combining computational and image-based data
“Methodologically, I think this is one of the most exciting examples of integrating spatially resolved transcriptomics and single-cell sequencing to create a new resource for the scientific community,” said John Marioni, Head of Research at EMBL-EBI. “It’s also work we can build upon to include more target genes across different stages of development.”
The researchers carried out this study using 8–12 somite stage mouse embryos. This stage of development was of particular interest because it is when the cells within the embryo start to differentiate, or become a specific cell type. The researchers applied an image-based single-cell transcriptomics method – seqFISH (developed by collaborators at Caltech) – to detect 387 target genes. They combined this information with scRNAseq data to produce an atlas of cell types found across this stage of mouse development.
“For this study we needed to process, analyse and integrate a lot of data sets to enable us to map the identities of cells onto a spatial reference,” says Shila Ghazanfar, Research Associate at CRUK Cambridge Institute. “This new approach means that we can take a section of the embryo and essentially paint on the cell types using different colours to place cell type context on the anatomy of the embryo at single-cell resolution.”
Insights into brain and gut development
Tim Lohoff, a PhD student at the Babraham Institute and lead author on the paper, commented: “Previously, researchers have been able to measure gene expression profiles for embryonic cells. However, it has long been a technological challenge to link these profiles to their original spatial location. Our work has been able to overcome this challenge, providing critical information about how the spatial environments of cells are critical to organ development, and opening up new avenues of research.”
The researchers were able to use the Spatial Mouse Atlas they created to uncover new insights into mouse development. They were able to find previously unreported gene expression information within the developing brain and gut tube of the mouse. This new approach provides a robust framework for future studies looking at spatial gene expression, both in the mouse and potentially other biological systems.
“This landmark study has already allowed us to pinpoint some of the molecular events that lead to the development of organs in mice. By providing a more detailed blueprint for development shared between mammals, this study could help to further advance the possibility of generating cell types in a dish for regenerative medicine.” says Professor Wolf Reik, Group leader in the Epigenetics research programme.
This news item is adapted from a press release produced by the EMBL’s European Bioinformatics Institute (EMBL-EBI). To get in touch with their press team please email firstname.lastname@example.org
Contact at the Babraham Institute
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Lohoff T., et al. (2021). Integration of spatial and single cell transcriptomic data elucidates mouse organogenesis. Nature Biotechnology
Affiliated authors (in author order):
Tim Lohoff, PhD student, Reik labWolf Reik, Group leader in the Epigenetics research programme
Header image: a globe
In text gif: At first cells are positioned according to the UMAP coordinates associated with their gene expression profiles, coloured by their associated cell types, the cells then reposition into their physical coordinates as measured using the seqFISH platform.
This research was funded by the Wellcome Trust, the University of Cambridge,, the Nation Institute for Health, the Royal Society, the Swedish Research Council, and core funding from the MRC and Wellcome Trust and Cancer Research UK.
Reik lab research page
News 20th February 2019: Establishing the molecular blueprint of early embryo development
Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here was performed at the Gurdon Institute. Wild type mice were bread and embryos were collected 8 days after fertilisation and prepared for imaging.
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About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
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06 September 2021