Vitamin B12 partially rescues embryonic cell migration defects in C. elegans ephrin mutants by improving propionic acid breakdown and one-carbon cycle metabolism.

Abstract

Successful cell migration followed by cell adhesion and tissue remodeling is required for organogenesis in a number of tissues, many of which are susceptible to gene-environment interactions resulting in congenital anomalies. In C. elegans embryogenesis, one such event is the closure of the ventral cleft, an essential first step in morphogenesis; this process depends on ephrin signaling, but no single gene mutation is fully penetrant embryonic lethal, likely due to redundancy with semaphorin and Robo signaling. We exposed hermaphrodites mutant for vab-1, the C. elegans ephrin receptor, to various environmental conditions and found vitamin B12 supplementation could partially rescue the embryonic lethality of multiple alleles improving survival by 58%. Vitamin B12 improved the frequency of ventral cleft closure by promoting cell positions more similar to wildtype and increasing cell migration. We found vitamin B12 partially rescued the embryonic lethality of other ephrin pathway mutants as well as semaphorin and robo mutants, but not mutants with ventral cleft defects due to cell adhesion or cell fate defects. We found rescue by vitamin B12 depends on its functions in both mitochondrial propionic acid breakdown and the one-carbon cycle, and antioxidant treatment can also partially rescue ephrin pathway mutants. These results are distinct from the larval response to vitamin B12, which depends only on the one-carbon cycle, emphasizing the unique metabolism of embryos and particularly the metabolic needs of migrating cells. Overall, our findings highlight the C. elegans embryo as a model system to investigate gene-environment interactions and developmental metabolism.