Antagonistic Activities of Sox2 and Brachyury Control the Fate Choice of Neuro-Mesodermal Progenitors

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 yet been revealed. Here we present a global analysis of NMPs and their descending lineages performed on purified cells from embryonic day 8.5 wild-type and mutant embryos. We show that T, cooperatively with WNT signaling, controls the progenitor state and the switch toward the mesodermal fate. Sox2 acts antagonistically and promotes neural development. T is also involved in remodeling the chromatin for mesodermal development. Tbx6 reinforces the mesodermal fate choice, represses the progenitor state, and confers paraxial fate commitment. Our findings refine previous models and establish molecular principles underlying mammalian trunk development, comprising NMP maintenance, lineage choice, and mesoderm formation. •Brachyury is essential for the maintenance of neuro-mesodermal progenitors•Sox2 and Brachyury antagonistically control the neural versus mesodermal fate choice•Brachyury is essential for chromatin remodeling promoting the mesodermal lineage•Tbx6 sustains the mesodermal lineage choice and commits cells to the paraxial fate The mammalian trunk arises from neuro-mesodermal progenitors (NMPs) giving rise to two fundamentally different cell lineages, one forming the spinal cord and the other mesodermal tissues. Analyzing the lineages derived from NMPs, Koch et al. find antagonistic roles for Sox2 and Brachyury in the specification of neural and mesodermal fates.