Spatiotemporal structure of cell fate decisions in murine neural crest
Abstract
Neural crest cells are embryonic progenitors that generate numerous cell types in vertebrates. With single-cell analysis, we show that mouse trunk neural crest cells become biased toward neuronal lineages when they delaminate from the neural tube, whereas cranial neural crest cells acquire ectomesenchyme potential dependent on activation of the transcription factor Twist1. The choices that neural crest cells make to become sensory, glial, autonomic, or mesenchymal cells can be formalized as a series of sequential binary decisions. Each branch of the decision tree involves initial coactivation of bipotential properties followed by gradual shifts toward commitment. Competing fate programs are coactivated before cells acquire fate-specific phenotypic traits. Determination of a specific fate is achieved by increased synchronization of relevant programs and concurrent repression of competing fate programs.
Additional Information
© 2019 American Association for the Advancement of Science. Received 9 January 2018; resubmitted 12 December 2018. Accepted 10 April 2019. We thank the Eukaryotic Single Cell Genomics Facility for the single-cell RNA-seq and the in situ sequencing pilot facility at the Science for Life Laboratory, Sweden (for technical assistance with the in situ sequencing experiments). We also thank O. Kharchenko for help with illustrations and V. Petukhov for assistance with computational analysis of in situ sequencing data. Funding: I.A. was funded by a Swedish Research Council (Vetenskapsradet, VR) grant, ERC Consolidator grant "STEMMING-FROM-NERVE" N647844, the Paradifference Foundation, and the Bertil Hallsten Research Foundation. P.V.K. was supported by NSF-14-532 CAREER award and NIH R01HL131768. M.N. was funded by a Swedish Research Council (Vetenskapsradet) grant 2016-03645, the Knut and Alice Wallenberg Foundation, and Familjen Erling Perssons stiftelse. V.D. was supported by a Russian Science Foundation grant (18-75-10005, immunochemistry) and the Swedish Research Council (2015-03387). M.E.K. was supported by Stiftelsen Riksbankens Jubileumsfond (Erik Rönnbergs fond stipend). N.A. was supported by RSF grant 16-15-10237. Author contributions: M.K., M.E.K., J.P., L.E., N.A., Y.Y., M.H., V.D., M.F., M.L.P., F.B., C.Y., X.Q., W.-Y.H., and L.C. acquired all biological data and performed the relevant analysis. R.S., P.V.K., and T.C. performed computational analysis of single-cell data. R.S. and P.V.K. developed computational methods. R.S. and M.M.H. performed computational analysis of in situ sequencing data. C.B., M.N., M.E.B., D.A.G., J.-F.B., G.G.C., P.E., K.F., P.V.K., and I.A. gave feedback on experimental aspects, supervised experimental approaches, and implemented the data interpretation. R.S., M.K., M.E.K., and J.P. made all figures containing data and resulting analysis (except Fig. 7). R.S., M.K., M.E.K., P.V.K., and I.A. designed the study, organized experimental work, and wrote the manuscript. All authors provided feedback on figures, manuscript composition, and structure. Competing interests: M.N. holds shares in Cartana AB, a company commercializing in situ sequencing reagents. Other authors declare no conflicts of interest. Data and materials availability: All single-cell RNA-seq datasets have been deposited in the GEO under accession code GSE129114. Processed data, code, supplementary materials, and interactive views of datasets can be accessed on the authors' website: http://pklab.med.harvard.edu/ruslan/neural.crest.html. These URLs will be maintained exactly as they are for at least 5 years with no changes. The Sox10^(CreERT2) strain is available from the laboratory of Vassilis Pachnis (The Francis Crick Institute, UK) under a material transfer agreement with the institution. All other data needed to evaluate the conclusions in the paper are present in the paper or the supplementary materials.Attached Files
Published - eaas9536.full.pdf
Supplemental Material - aas9536_DataS1_to_S12.zip
Supplemental Material - aas9536_TablesS1_to_S11.zip
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Additional details
- Eprint ID
- 96200
- Resolver ID
- CaltechAUTHORS:20190607-090122437
- 647844
- European Research Council (ERC)
- Paradifference Foundation
- Bertil Hallsten Research Foundation
- 14-532
- NSF
- R01HL131768
- NIH
- 2016-03645
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- Familjen Erling Perssons
- 18-75-10005
- Russian Science Foundation
- 2015-03387
- Swedish Research Council
- Stiftelsen Riksbankens Jubileumsfond
- 16-15-10237
- Russian Science Foundation
- Created
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2019-06-07Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field