A single-embryo, single-cell time-resolved model for mouse gastrulation

Abstract

Summary Mouse embryonic development is a canonical model system for studying mammalian cell fate acquisition. Recently, single-cell atlases comprehensively charted embryonic transcriptional landscapes, yet inference of the coordinated dynamics of cells over such atlases remains challenging. Here, we introduce a temporal model for mouse gastrulation, consisting of data from 153 individually sampled embryos spanning 36 h of molecular diversification. Using algorithms and precise timing, we infer differentiation flows and lineage specification dynamics over the embryonic transcriptional manifold. Rapid transcriptional bifurcations characterize the commitment of early specialized node and blood cells. However, for most lineages, we observe combinatorial multi-furcation dynamics rather than hierarchical transcriptional transitions. In the mesoderm, dozens of transcription factors combinatorially regulate multifurcations, as we exemplify using time-matched chimeric embryos of Foxc1/Foxc2 mutants. Our study rejects the notion of differentiation being governed by a series of binary choices, providing an alternative quantitative model for cell fate acquisition.

Conserved Structure and Evolution of DPF Domain of PHF10—The Specific Subunit of PBAF Chromatin Remodeling Complex

“…In mammals, the expression of PHF10 begins at the earliest stages of embryonic development: during gastrulation, PHF10 isoforms can be detected in all future organs and tissues ( Figure 1 ) [ 20 ]. This protein is vitally important for embryogenesis, as PHF10 knockout is embryonically lethal [ 21 ].…”

A continuous model of early mammalian development

“…Although studied for more than 150 years, many aspects of gastrulation remain elusive, not least a comprehensive understanding of the molecular factors governing the specification of the many cell lineages that emerge from this process. Writing in Cell, Mittnenzweig et al 1 densely sample gene expression in gastrulating mouse embryos over a 36-hour window and construct a continuous model of cell-lineage specification.…”

“…In this context, Mittnenzweig et al set out to generate a continuous representation of cellstate dynamics during mouse gastrulation 1 . They applied scRNA-seq to 153 mouse embryos from E6.5 to E8.1, altogether profiling gene expression in about 33,000 individual cells.…”

“…Crohn's disease, a chronic inflammatory bowel disease, affects many people. For example, more than 0.3% of the populations of Canada and Germany have the condition, and its incidence is increasing worldwide 1 . Better therapies are needed, but progress in treating Crohn's disease has been hampered by the lack of understanding of how it arises.…”

“…Figure 1 | A continuous-flow model of mouse gastrulation. Mittnenzweig et al1 profiled the RNA contents of cells from mouse embryos during gastrulation, a process during which a single cell layer called the epiblast transforms into three layers: ectoderm, endoderm and mesoderm. In doing so, the authors generated a model of gastrulation that is continuous over time, showing the transitions between different cell types; a simplified version is shown here.…”