Fig. 7. Schematic showing how a branching model of lineage decisions in the ENS underpins the neurogenic potential of adult glia.

ANCCs become ENS progenitors upon invasion of the foregut. A default differentiation trajectory, that maintains a relatively continuous directionality of gene expression change, gives rise to mature enteric glia. Neurogenic trajectories branch off from this default trajectory during embryonic and early postnatal time points. As cells transit along the default ENS progenitor-glia axis neurogenic output diminishes until it ceases in adult animals at homeostasis. Accordingly, transcriptional modules that underlie active neurogenic activity (e.g. GM 16) are downregulated, whereas those related to glial maturation and immune function (e.g. GM75) are upregulated. In response to changes in the environment (in vivo injury, culture conditions) glial cells can transit to upstream positions of their developmental axis and reactivate neurogenic transcriptional programmes. Figure created with BioRender.com.