This study demonstrates, for the first time, an essential function of IdoA in early embryonic development and cell migration in vivo. The spatio-temporal expression of Dse in the Xenopus embryo suggested a role of DS-epi1 in ectoderm and NC development. The blockage of epimerase activity and IdoA biosynthesis upon the knockdown of DS-epi1 did not affect the allocation of neural and epidermal fates or the formation of NC progenitors. However, DS-epi1 deficiency altered the expression of neural-plate-border- and NC-specific transcription factors and decreased the extent of NC cell migration, which led to defects in craniofacial skeleton, melanocyte and dorsal fin formation. The functional links between DS-epi1 and EMT and between DS-epi1 cell adhesion on fibronectin, as established in this study for normal NC development, might have implications for neurocristopathies and cancer.