- Chan, Michelle M;
- Smith, Zachary D;
- Grosswendt, Stefanie;
- Kretzmer, Helene;
- Norman, Thomas M;
- Adamson, Britt;
- Jost, Marco;
- Quinn, Jeffrey J;
- Yang, Dian;
- Jones, Matthew G;
- Khodaverdian, Alex;
- Yosef, Nir;
- Meissner, Alexander;
- Weissman, Jonathan S
Ontogeny describes the emergence of complex multicellular organisms from single totipotent cells. This field is particularly challenging in mammals, owing to the indeterminate relationship between self-renewal and differentiation, variation in progenitor field sizes, and internal gestation in these animals. Here we present a flexible, high-information, multi-channel molecular recorder with a single-cell readout and apply it as an evolving lineage tracer to assemble mouse cell-fate maps from fertilization through gastrulation. By combining lineage information with single-cell RNA sequencing profiles, we recapitulate canonical developmental relationships between different tissue types and reveal the nearly complete transcriptional convergence of endodermal cells of extra-embryonic and embryonic origins. Finally, we apply our cell-fate maps to estimate the number of embryonic progenitor cells and their degree of asymmetric partitioning during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems, which will facilitate the construction of a quantitative framework for understanding developmental processes.