Neural progenitors adopt specific identities by directly repressing all alternative progenitor transcriptional programmes

In the vertebrate neural tube, a morphogen-induced transcriptional network produces multiple molecularly distinct progenitor pools arranged in discrete spatial domains, each generating different neuronal subtypes. To determine how the network generates and maintains unique cellular identities, we established an in vitro differentiation system to define gene expression signatures of distinct progenitor populations. In parallel, we identified direct gene-regulatory inputs corresponding to locations of transcription factor binding. Combined with targeted perturbations of the network, this revealed a mechanism in which a progenitor identity is installed by active repression of the entire transcriptional programmes of all other neural progenitor fates. In the ventral neural tube, sonic hedgehog (Shh) signalling together with broadly expressed transcriptional activators directly and concurrently activates the gene expression programmes of several domains. The specific outcome is selected by repressive input provided by Shh-induced transcription factors that act as the key nodes in the network enabling progenitors to adopt a single definitive identity from several initially permitted options. Together the data suggest design principles relevant to many developing tissues.