Enteric nervous system development relies on intestinal colonization by enteric neural
crest-derived cells (ENCDCs). This is driven by a population of highly migratory and
proliferative ENCDC at the wavefront, but the molecular characteristics of these cells
are unknown. ENCDCs from the wavefront and the trailing region were isolated and subjected
to RNA-seq. Wavefront-ENCDCs were transcriptionally distinct from trailing ENCDCs,
and temporal modelling confirmed their relative immaturity. This population of ENCDCs
exhibited altered expression of ECM and cytoskeletal genes, consistent with a migratory
phenotype. Unlike trailing ENCDCs, the wavefront lacked expression of genes related
to neuronal or glial maturation. Since wavefront ENCDC genes were associated with
migration and developmental immaturity, the genes that remain expressed in later progenitor
populations may be particularly pertinent to understand the maintenance of ENCDC progenitor
characteristics. Dusp6 expression was specifically upregulated at the wavefront. Inhibiting
DUSP6 activity prevented wavefront colonization of the hindgut, and inhibited the
migratory ability of post-colonized ENCDCs from midgut and postnatal neurospheres.
These effects were reversed by simultaneous inhibition of ERK signaling, indicating
that DUSP6-mediated ERK inhibition is required for ENCDC migration.
