Mitochondrial dysfunction interferes with neural crest specification through the FoxD3 transcription factor.

The neural crest is an important group of cells with pluripotency and migratory ability that is crucially involved in tissue and cell specification during development. Craniofacial shaping, sensory neurons, body asymmetry, and pigmentation are linked to neural crest functionality. Despite its prominent role in embryogenesis, neural crest specification as well as the possible part mitochondria play in such a process remains unclarified. Mitochondria are important organelles not only for respiration, but also for regulation of cell proliferation, differentiation and death. Modulation of mitochondrial fitness and depletion of mitochondrial ATP synthesis has been shown to down-regulate Wnt signaling, both in vitro and in vivo. Since Wnt signaling is one of the crucial players during neural crest induction/specification, we hypothesized a signaling cascade connecting mitochondria to embryonic development and neural crest migration and differentiation. Here, by using pharmacological and genetic modulators of mitochondrial function, we provide evidence that a crosstalk between mitochondrial energy homeostasis and Wnt signaling is important in the development of neural crest-derived tissues. Furthermore, our results highlight the possibility to modulate neural crest cell specification by tuning mitochondrial metabolism via FoxD3, an important transcription factor that is regulated by Wnt. FoxD3 ensures the correct embryonic development and contributes to the maintenance of cell stemness and to the induction of epithelial-to-mesenchymal transition. In summary, our work offers new insights into the molecular mechanism of action of FoxD3 and demonstrates that mitochondrial fitness is linked to the regulation of this important transcription factor via Wnt signaling in the context of neural crest specification.