A single-cell molecular map of mouse gastrulation and early organogenesis

Blanca Pijuan-Sala; Jonathan A. Griffiths; Carolina Guibentif; Tom W. Hiscock; Wajid Jawaid; Fernando J. Calero-Nieto; Carla Mulas; Ximena Ibarra-Soria; Richard C.V. Tyser; Debbie Lee Lian Ho; Wolf Reik; Shankar Srinivas; Benjamin D. Simons; Jennifer Nichols; John C. Marioni; Berthold Göttgens

doi:10.1038/s41586-019-0933-9

A single-cell molecular map of mouse gastrulation and early organogenesis

Blanca Pijuan-Sala, Jonathan A. Griffiths, Carolina Guibentif, Tom W. Hiscock, Wajid Jawaid, Fernando J. Calero-Nieto, Carla Mulas, Ximena Ibarra-Soria, Richard C.V. Tyser, Debbie Lee Lian Ho, Wolf Reik, Shankar Srinivas, Benjamin D. Simons, Jennifer Nichols, John C. Marioni, Berthold Göttgens^*

^*Corresponding author for this work

Randall Centre of Cell & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

507 Citations (Scopus)

Abstract

Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1 ^−/− chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.

Original language	English
Pages (from-to)	490-495
Number of pages	6
Journal	Nature
Volume	566
Issue number	7745
DOIs	https://doi.org/10.1038/s41586-019-0933-9
Publication status	Published - 28 Feb 2019

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Pijuan-Sala, B., Griffiths, J. A., Guibentif, C., Hiscock, T. W., Jawaid, W., Calero-Nieto, F. J., Mulas, C., Ibarra-Soria, X., Tyser, R. C. V., Ho, D. L. L., Reik, W., Srinivas, S., Simons, B. D., Nichols, J., Marioni, J. C., & Göttgens, B. (2019). A single-cell molecular map of mouse gastrulation and early organogenesis. Nature, 566(7745), 490-495. https://doi.org/10.1038/s41586-019-0933-9

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title = "A single-cell molecular map of mouse gastrulation and early organogenesis",

abstract = " Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1 −/− chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine. ",

author = "Blanca Pijuan-Sala and Griffiths, {Jonathan A.} and Carolina Guibentif and Hiscock, {Tom W.} and Wajid Jawaid and Calero-Nieto, {Fernando J.} and Carla Mulas and Ximena Ibarra-Soria and Tyser, {Richard C.V.} and Ho, {Debbie Lee Lian} and Wolf Reik and Shankar Srinivas and Simons, {Benjamin D.} and Jennifer Nichols and Marioni, {John C.} and Berthold G{\"o}ttgens",

note = "Funding Information: Acknowledgements We thank W. Mansfield for blastocyst injections; A. T. L. Lun and F. Hamey for discussions concerning the analysis; T. L. Hamilton for technical support in embryo collection; S. Kinston and K. Jones for technical assistance; the Flow Cytometry Core Facility at CIMR for cell sorting; the CRUK-CI genomics core for the chimaera scRNA-seq 10x libraries and for letting us use the 10x Chromium after hours; the Wellcome Sanger Institute DNA Pipelines Operations for sequencing; and K. Hadjantonakis for sharing the Ttr::cre mouse line. Research in the authors{\textquoteright} laboratories is supported by Wellcome, the MRC, CRUK, Bloodwise, and NIH-NIDDK; by core support grants from Wellcome to the Cambridge Institute for Medical Research and Wellcome-MRC Cambridge Stem Cell Institute; and by core funding from CRUK and the European Molecular Biology Laboratory. B.P.-S. and D.L.L.H. are funded by the Wellcome 4-Year PhD Programme in Stem Cell Biology and Medicine and the University of Cambridge; D.L.L.H. is also funded by the Cambridge Commonwealth European and International Trust. J.A.G. is funded by the Wellcome Mathematical Genomics and Medicine Programme at the University of Cambridge (109081/Z/15/A). C.G. is funded by the Swedish Research Council (2017-06278, administered by Sahlgrenska Cancer Center, University of Gothenburg). This work was funded as part of a Wellcome Strategic Award (105031/Z/14/Z) awarded to W.R., B.G., J.C.M., J.N., L. Vallier, S.S., B.D.S., S. Teichmann, and T. Voet; by a Wellcome grant (108438/Z/15) awarded to J.C.M. and S.S., and by a BBSRC grant (BBS/E/B/000C0421) awarded to W.R. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = feb,

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doi = "10.1038/s41586-019-0933-9",

language = "English",

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Pijuan-Sala, B, Griffiths, JA, Guibentif, C, Hiscock, TW, Jawaid, W, Calero-Nieto, FJ, Mulas, C, Ibarra-Soria, X, Tyser, RCV, Ho, DLL, Reik, W, Srinivas, S, Simons, BD, Nichols, J, Marioni, JC & Göttgens, B 2019, 'A single-cell molecular map of mouse gastrulation and early organogenesis', Nature, vol. 566, no. 7745, pp. 490-495. https://doi.org/10.1038/s41586-019-0933-9

TY - JOUR

T1 - A single-cell molecular map of mouse gastrulation and early organogenesis

AU - Pijuan-Sala, Blanca

AU - Griffiths, Jonathan A.

AU - Guibentif, Carolina

AU - Hiscock, Tom W.

AU - Jawaid, Wajid

AU - Calero-Nieto, Fernando J.

AU - Mulas, Carla

AU - Ibarra-Soria, Ximena

AU - Tyser, Richard C.V.

AU - Ho, Debbie Lee Lian

AU - Reik, Wolf

AU - Srinivas, Shankar

AU - Simons, Benjamin D.

AU - Nichols, Jennifer

AU - Marioni, John C.

AU - Göttgens, Berthold

N1 - Funding Information: Acknowledgements We thank W. Mansfield for blastocyst injections; A. T. L. Lun and F. Hamey for discussions concerning the analysis; T. L. Hamilton for technical support in embryo collection; S. Kinston and K. Jones for technical assistance; the Flow Cytometry Core Facility at CIMR for cell sorting; the CRUK-CI genomics core for the chimaera scRNA-seq 10x libraries and for letting us use the 10x Chromium after hours; the Wellcome Sanger Institute DNA Pipelines Operations for sequencing; and K. Hadjantonakis for sharing the Ttr::cre mouse line. Research in the authors’ laboratories is supported by Wellcome, the MRC, CRUK, Bloodwise, and NIH-NIDDK; by core support grants from Wellcome to the Cambridge Institute for Medical Research and Wellcome-MRC Cambridge Stem Cell Institute; and by core funding from CRUK and the European Molecular Biology Laboratory. B.P.-S. and D.L.L.H. are funded by the Wellcome 4-Year PhD Programme in Stem Cell Biology and Medicine and the University of Cambridge; D.L.L.H. is also funded by the Cambridge Commonwealth European and International Trust. J.A.G. is funded by the Wellcome Mathematical Genomics and Medicine Programme at the University of Cambridge (109081/Z/15/A). C.G. is funded by the Swedish Research Council (2017-06278, administered by Sahlgrenska Cancer Center, University of Gothenburg). This work was funded as part of a Wellcome Strategic Award (105031/Z/14/Z) awarded to W.R., B.G., J.C.M., J.N., L. Vallier, S.S., B.D.S., S. Teichmann, and T. Voet; by a Wellcome grant (108438/Z/15) awarded to J.C.M. and S.S., and by a BBSRC grant (BBS/E/B/000C0421) awarded to W.R. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/2/28

Y1 - 2019/2/28

N2 - Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1 −/− chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.

AB - Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1 −/− chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.

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U2 - 10.1038/s41586-019-0933-9

DO - 10.1038/s41586-019-0933-9

M3 - Article

C2 - 30787436

AN - SCOPUS:85062300354

SN - 0028-0836

VL - 566

SP - 490

EP - 495

JO - Nature

JF - Nature

IS - 7745

ER -

A single-cell molecular map of mouse gastrulation and early organogenesis

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