Antagonistic activities of Sox2 and Brachyury control the fate choice of neuro-mesodermal progenitors. Mus musculus

The spinal cord and mesodermal tissues of the trunk such as the vertebral column and skeletal musculature derive from neuro-mesodermal progenitors (NMPs). Sox2, Brachyury (T) and Tbx6 have been correlated with NMP potency and lineage choice, however, their exact role and interaction in these processes have not been revealed yet. Here we present a global analysis of NMPs and their descending lineages performed on purified cells from E8.5 wild-type and mutant embryos. We show that T, cooperatively with WNT signaling, controls the progenitor state and the switch towards the mesodermal fate. Sox2 acts antagonistically and promotes neural development. Tbx6 reinforces the mesodermal fate choice, represses the progenitor state and confers paraxial fate commitment. Our findings refine previous models and establish new concepts of the molecular principles of mammalian trunk development comprising NMP maintenance, lineage choice and mesoderm formation. Overall design: Bulk transcriptomes (RNA-Seq) and chromatin accessibility (ATAC-Seq) from T/Sox2 expressing subpopulations isolated during trunk development from wildtype and T knock-out mouse embryos. Data is supplemented by Fluidigm single-cell RNA-Seq for T/Sox2 co-expressing cells from wildtype embryos and a bulk RNA-Seq comparison of wildtype and Tbx6 knock-out mouse embryos. ChIP-Seq for T, Sox2, Tbx6 and beta-catenin has been performed with chromatin from in vitro differentiated neuromesodermal progenitors and presomitic mesoderm.