Primitive to visceral endoderm maturation is essential for mouse epiblast survival beyond implantation
Creators
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1.
University of Cambridge
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2.
California Institute of Technology
Abstract
The implantation of the mouse blastocyst initiates a complex sequence of tissue remodeling and cell differentiation events required for morphogenesis, during which the extraembryonic primitive endoderm transitions into the visceral endoderm. Through single-cell RNA sequencing of embryos at embryonic day 5.0, shortly after implantation, we reveal that this transition is driven by dynamic signaling activities, notably the upregulation of BMP signaling and a transient increase in Sox7 expression. Embryos deficient in Hepatocyte nuclear factor-1-beta (Hnf1b-/-), a gene critical for visceral endoderm differentiation, showed an interaction between visceral endoderm and epiblast, crucial for epiblast survival. Single-cell RNA profiling of Hnf1b-/- visceral endoderm shows developmental delays and severe dysregulation in several nutrient transport pathways. Impaired glucose uptake in Hnf1b-/- embryos suggests that the activation of nutrient transport mechanisms during the primitive-to-visceral endoderm transition may be vital for post-implantation epiblast development. These findings offer new insights into the molecular regulation of early mammalian development.
Copyright and License
© 2024 Published by Elsevier Inc. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
Acknowledgement
We thank C. Gantner and B. Weatherbee for critical feedback on the article, C. Ross for help in project conceptualization, feedback on the article and help with the immunosurgery experiments. This project has been made possible through the following grants to MZG: European Research Council (669198), the Wellcome Trust (207415/Z/17/Z), NIH Pioneer Award Fund (DP1 HD104575-01), Open Philanthropy/Silicon Valley Community Foundation. A.W. was supported by the EU Horizon 2020 Marie Sklodowska-Curie actions grant (ImageInLife, 721537) to M.Z.G. The T.B. lab is funded by the Wellcome Trust (WT RG89228) and the Centre for Trophoblast Research, University of Cambridge. T.B. is a WT-Royal Society Sir Henry Dale Fellow (WT RG89228).
Data Availability
Data and code availability
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The E5.0 WT and KO single-cell RNA-seq datasets generated in this study are available in the ArrayExpress repository: “E-MTAB-11140”.
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Code used in this project is provided at https://github.com/dsiriwardena/Visceral-Endoderm-differentiation-is-mediated-by-Hnf1B-and-is-required-for-epiblast-survival.
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The original dataset of mouse immunofluorescence images and live imaging files are available upon reasonable request through the lead contact. Requests for additional, more detailed information or resources should be directed to and will be fulfilled by the lead contact Dr. Magdalena Zernicka-Goetz (mz205@cam.ac.uk).
Supplemental Material
Supplemental material attached.
- Document S1. Figures S1–S14.
- Table S1. List of marker genes used for lineage assignment, related to Figure 1. Full list of marker genes assessed for Figure 1C.
- Table S2. Differentially expressed genes between E4.5 to E5.0 and E5.0 to E5.5 PE/VE lineages, related to Figure 1. Full list of differentially expressed genes visualized in Figure 1D/E.
- Table S3. Differentially expressed genes between WT PE/VE and Hnf1b KO VE, related to Figure 6. Full list of differentially expressed genes visualized in Figure 6B.
- Table S4. QC Table, related to Figure 1. QC table including lineage annotations for our single cell sequencing dataset.
Files
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Additional details
Identifiers
- PMCID
- PMC11761342
- PMID
- 39868030
Funding
- Wellcome Trust
- WT-Royal Society Sir Henry Dale Fellow WT RG89228
- European Commission
- EU Horizon 2020 Marie Sklodowska-Curie actions grant 721537
- National Institutes of Health
- DP1 HD104575-01
- Wellcome Trust
- 207415/Z/17/Z
- University of Cambridge
- Centre for Trophoblast Research
- European Research Council
- 669198
- Silicon Valley Community Foundation
Dates
- Available
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2025-01-07Version of record
Caltech Custom Metadata
- Caltech groups
- Division of Biology and Biological Engineering (BBE)
- Publication Status
- Published