Regional specific metabolism regulates specification of the Spemann Organizer

Project Summary Congenital heart disease is a major cause of illness in newborns and children. While studying Leigh’s syndrome, a mitochondrial metabolism disease caused by LRPPRC that also causes congenital heart disease and heterotaxy, we were surprised to discover that regional metabolism in the early Xenopus embryo dictates cell fate. We found that the Spemann-Mangold Organizer (the Organizer) depends on regional metabolism. In fact, our work demonstrates that Hif-1α regulates the specification of the Organizer and that the Organizer consumes 20% more oxygen than more ventral (non-Organizer) tissue. To reconcile an increase in oxygen consumption and activation of Hif-1α, we discovered that the Organizer has “leak” metabolism, which we have proposed previously in our group to be caused by the c-subunit of the ATP Synthase. This proposal investigates a signaling pathway that connects canonical Wnt signaling, Hif-1α, and regional metabolism to understand an iconic signaling center, the Spemann-Mangold Organizer.