Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis.

Clonal lineage information is fundamental in revealing cell fate choices. Using genetic single-cell labeling in utero, we investigated lineage segregations during anteroposterior axis formation in mouse. We show that while endoderm and surface ectoderm segregate during gastrulation, neural ectoderm and mesoderm share a common progenitor persisting through all stages of axis elongation. These data challenge the paradigm that the three germ layers, formed by gastrulation, constitute the primary branchpoints in differentiation of the pluripotent epiblast toward tissue-specific precursors. Bipotent neuromesodermal progenitors show self-renewing characteristics and may represent the cellular substrate coupling sustained axial elongation and coordinated differentiation of these tissues. These findings have important implications for the interpretation of the phenotypic defects of several mouse mutants and the directed differentiation of embryonic stem (ES) cells in vitro.