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

Abstract

Successful cell migration followed by tissue fusion is required for organogenesis in a number of tissues, many of which are susceptible to gene-environment interactions that can result in congenital anomalies. In C. elegans embryogenesis, one such event is the closure of the ventral cleft, which must occur as the first step in morphogenesis, otherwise embryos arrest; this process depends on ephrin signaling, but no single gene mutation is fully penetrant embryonic lethal. We exposed hermaphrodites mutant for vab-1, the C. elegans ephrin receptor, to various environmental conditions and found that vitamin B12 supplementation could partially rescue the embryonic lethality of multiple alleles from 40% survival to 63% survival. Analysis of vab-1 mutant phenotypes showed that vitamin B12 reduced the frequency of ventral cleft closure failure by promoting more normal cell positions and increased migration by the precursor cells of those that adhere to close the cleft. We found that vitamin B12 partially rescued the embryonic lethality of other ephrin pathway mutants, but not mutants that have ventral cleft defects due to cell adhesion or cell fate defects. We found that rescue by vitamin B12 depends on its functions in both mitochondrial propionic acid breakdown and the one-carbon cycle, and that 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 a model system to investigate gene-environment interactions and developmental metabolism.