{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T01:18:06Z","timestamp":1768094286766,"version":"3.49.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"CCHMC Trustee Award"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R00 GM111825"],"award-info":[{"award-number":["R00 GM111825"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 Caenorhabditis 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 wild type 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.<\/jats:p>","DOI":"10.1093\/genetics\/iyaf054","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T08:58:11Z","timestamp":1744361891000},"source":"Crossref","is-referenced-by-count":1,"title":["Vitamin B12 partially rescues embryonic cell migration defects in <i>Caenorhabditis elegans<\/i> ephrin mutants by improving propionic acid breakdown and one-carbon cycle metabolism"],"prefix":"10.1093","volume":"230","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-1572","authenticated-orcid":false,"given":"Tushar H","family":"Ganjawala","sequence":"first","affiliation":[{"name":"Divisions of Pulmonary Biology and Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary Biology and Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prativa","family":"Amom","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary Biology and Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radmehr","family":"Molaei","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary Biology and Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary Biology and Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4818-916X","authenticated-orcid":false,"given":"Amanda L","family":"Zacharias","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary Biology and Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["USA"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, University of Cincinnati , Cincinnati, OH 45267 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"issue":"1","key":"2025060408313332600_iyaf054-B1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s40748-022-00139-9","article-title":"Evidence based recommendations for an optimal prenatal supplement for women in the US: vitamins and related nutrients","volume":"8","author":"Adams","year":"2022","journal-title":"Matern Health Neonatol Perinatol"},{"issue":"2","key":"2025060408313332600_iyaf054-B2","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.celrep.2018.12.064","article-title":"A persistence detector for metabolic network rewiring in an animal","volume":"26","author":"Bulcha","year":"2019","journal-title":"Cell Rep"},{"issue":"23","key":"2025060408313332600_iyaf054-B3","doi-asserted-by":"publisher","first-page":"5499","DOI":"10.1242\/dev.00122","article-title":"The divergent C. elegans ephrin EFN-4 functions inembryonic morphogenesis in a pathway independent of the VAB-1 Eph receptor","volume":"129","author":"Chin-Sang","year":"2002","journal-title":"Development"},{"key":"2025060408313332600_iyaf054-B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1895\/wormbook.1.35.1","volume-title":"Epidermal Morphogenesis","author":"Chisholm","year":"2005"},{"key":"2025060408313332600_iyaf054-B5","doi-asserted-by":"publisher","first-page":"RP87099","DOI":"10.7554\/eLife.87099","article-title":"Gene regulatory patterning codes in early cell fate specification of the C. elegans embryo","volume":"12","author":"Cole","year":"2024","journal-title":"Elife"},{"issue":"6","key":"2025060408313332600_iyaf054-B6","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.devcel.2022.02.019","article-title":"Localized glucose import, glycolytic processing, and mitochondria generate a focused ATP burst to power basement-membrane invasion","volume":"57","author":"Garde","year":"2022","journal-title":"Dev Cell"},{"issue":"5","key":"2025060408313332600_iyaf054-B7","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/s0092-8674(00)81131-9","article-title":"The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis in C. elegans","volume":"92","author":"George","year":"1998","journal-title":"Cell"},{"issue":"16","key":"2025060408313332600_iyaf054-B8","doi-asserted-by":"publisher","first-page":"3679","DOI":"10.1242\/dev.01947","article-title":"The VAB-1 Eph receptor tyrosine kinase and SAX-3\/Robo neuronal receptors function together during C. elegans embryonic morphogenesis","volume":"132","author":"Ghenea","year":"2005","journal-title":"Development"},{"issue":"3","key":"2025060408313332600_iyaf054-B9","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1534\/genetics.113.154393","article-title":"Mechanisms of ephrin receptor protein kinase-independent signaling in amphid axon guidance in Caenorhabditis elegans","volume":"195","author":"Grossman","year":"2013","journal-title":"Genetics"},{"issue":"1","key":"2025060408313332600_iyaf054-B10","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/s0896-6273(01)00448-2","article-title":"C. elegans slit acts in midline, dorsal-ventral, and anterior-posterior guidance via the SAX-3\/Robo receptor","volume":"32","author":"Hao","year":"2001","journal-title":"Neuron"},{"issue":"12","key":"2025060408313332600_iyaf054-B11","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1101\/gr.223735.117","article-title":"Genome-wide discovery of active regulatory elements and transcription factor footprints in Caenorhabditis elegans using DNase-seq","volume":"27","author":"Ho","year":"2017","journal-title":"Genome Res"},{"issue":"13","key":"2025060408313332600_iyaf054-B12","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1101\/gad.12.13.1947","article-title":"pha-4, an HNF-3 homolog, specifies pharyngeal organ identity in Caenorhabditis elegans","volume":"12","author":"Horner","year":"1998","journal-title":"Genes Dev"},{"key":"2025060408313332600_iyaf054-B13","doi-asserted-by":"publisher","first-page":"e37344","DOI":"10.7554\/eLife.37344","article-title":"Chromatin accessibility dynamics across C. elegans development and ageing","volume":"7","author":"J\u00e4nes","year":"2018","journal-title":"Elife"},{"issue":"1","key":"2025060408313332600_iyaf054-B14","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s12859-018-2127-0","article-title":"AceTree: a major update and case study in the long term maintenance of open-source scientific software","volume":"19","author":"Katzman","year":"2018","journal-title":"BMC Bioinformatics"},{"issue":"3","key":"2025060408313332600_iyaf054-B15","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.devcel.2018.12.018","article-title":"Adaptive F-actin polymerization and localized ATP production drive basement membrane invasion in the absence of MMPs","volume":"48","author":"Kelley","year":"2019","journal-title":"Dev Cell"},{"issue":"1","key":"2025060408313332600_iyaf054-B16","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1146\/annurev-cellbio-111315-125357","article-title":"Cell sheet morphogenesis: dorsal closure in Drosophila melanogaster as a model system","volume":"33","author":"Kiehart","year":"2017","journal-title":"Annu Rev Cell Dev Biol"},{"issue":"18","key":"2025060408313332600_iyaf054-B17","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1002\/bdr2.1606","article-title":"Genome-wide association studies of structural birth defects: a review and commentary","volume":"111","author":"Lupo","year":"2019","journal-title":"Birth Defects Res"},{"issue":"1","key":"2025060408313332600_iyaf054-B18","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.cell.2013.02.049","article-title":"Diet-induced developmental acceleration independent of TOR and insulin in C. elegans","volume":"153","author":"MacNeil","year":"2013","journal-title":"Cell"},{"issue":"1","key":"2025060408313332600_iyaf054-B19","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.ydbio.2005.11.019","article-title":"Characterization of loss-of-function and gain-of-function eph receptor tyrosine kinase signaling in C. elegans axon targeting and cell migration","volume":"290","author":"Mohamed","year":"2006","journal-title":"Dev Biol"},{"issue":"7","key":"2025060408313332600_iyaf054-B20","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1101\/gr.131920.111","article-title":"Multidimensional regulation of gene expression in the C. elegans embryo","volume":"22","author":"Murray","year":"2012","journal-title":"Genome Res"},{"issue":"5","key":"2025060408313332600_iyaf054-B21","doi-asserted-by":"publisher","first-page":"e1010187","DOI":"10.1371\/journal.pgen.1010187","article-title":"The anterior Hox gene ceh-13 and elt-1\/GATA activate the posterior Hox genes nob-1 and php-3 to specify posterior lineages in the C. elegans embryo","volume":"18","author":"Murray","year":"2022","journal-title":"PLoS Genet"},{"issue":"12","key":"2025060408313332600_iyaf054-B22","doi-asserted-by":"publisher","first-page":"3126","DOI":"10.1016\/j.celrep.2018.02.100","article-title":"C. elegans MRP-5 exports vitamin B12 from mother to offspring to support embryonic development","volume":"22","author":"Na","year":"2018","journal-title":"Cell Rep"},{"key":"2025060408313332600_iyaf054-B23","doi-asserted-by":"publisher","author":"Nawrocka","year":"2024","DOI":"10.1101\/2024.07.08.602367"},{"issue":"6459","key":"2025060408313332600_iyaf054-B24","doi-asserted-by":"publisher","first-page":"eaax1971","DOI":"10.1126\/science.aax1971","article-title":"A lineage-resolved molecular atlas of C. elegans embryogenesis at single-cell resolution","volume":"365","author":"Packer","year":"2019","journal-title":"Science"},{"issue":"4","key":"2025060408313332600_iyaf054-B25","doi-asserted-by":"publisher","first-page":"e3002057","DOI":"10.1371\/journal.pbio.3002057","article-title":"A D-2-hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development","volume":"21","author":"Ponomarova","year":"2023","journal-title":"PLoS Biol"},{"issue":"10","key":"2025060408313332600_iyaf054-B26","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1242\/dev.068338","article-title":"Mechanisms of tissue fusion during development","volume":"139","author":"Ray","year":"2012","journal-title":"Development"},{"issue":"1","key":"2025060408313332600_iyaf054-B27","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ydbio.2012.11.034","article-title":"A quantitative model of normal Caenorhabditis elegans embryogenesis and its disruption after stress","volume":"374","author":"Richards","year":"2013","journal-title":"Dev Biol"},{"issue":"1","key":"2025060408313332600_iyaf054-B28","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1186\/1471-2105-15-217","article-title":"A semi-local neighborhood-based framework for probabilistic cell lineage tracing","volume":"15","author":"Santella","year":"2014","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"2025060408313332600_iyaf054-B29","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1534\/genetics.117.300082","article-title":"Invading, leading and navigating cells in Caenorhabditis elegans: insights into cell movement in vivo","volume":"208","author":"Sherwood","year":"2018","journal-title":"Genetics"},{"issue":"1","key":"2025060408313332600_iyaf054-B30","doi-asserted-by":"publisher","first-page":"iyae050","DOI":"10.1093\/genetics\/iyae050","article-title":"WormBase 2024: status and transitioning to alliance infrastructure","volume":"227","author":"Sternberg","year":"2024","journal-title":"Genetics"},{"issue":"1","key":"2025060408313332600_iyaf054-B31","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/0012-1606(83)90201-4","article-title":"The embryonic cell lineage of the nematode Caenorhabditis elegans","volume":"100","author":"Sulston","year":"1983","journal-title":"Dev Biol."},{"issue":"4","key":"2025060408313332600_iyaf054-B32","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/S0092-8674(00)80530-9","article-title":"Wnt signaling polarizes an early C. elegans blastomere to distinguish endoderm from mesoderm","volume":"90","author":"Thorpe","year":"1997","journal-title":"Cell"},{"issue":"4","key":"2025060408313332600_iyaf054-B33","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.devcel.2016.07.025","article-title":"A transcriptional lineage of the early C","volume":"38","author":"Tintori","year":"2016","journal-title":"elegans Embryo. Dev Cell"},{"issue":"2","key":"2025060408313332600_iyaf054-B34","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.ydbio.2008.02.062","article-title":"Muscle cell migrations of C. elegans are mediated by the \u03b1-integrin INA-1, Eph receptor VAB-1, and a novel peptidase homologue MNP-1","volume":"318","author":"Tucker","year":"2008","journal-title":"Dev Biol."},{"issue":"1","key":"2025060408313332600_iyaf054-B35","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.ydbio.2011.07.026","article-title":"Membrane extensions are associated with proper anterior migration of muscle cells during Caenorhabditis elegans embryogenesis","volume":"358","author":"Viveiros","year":"2011","journal-title":"Dev Biol"},{"issue":"3","key":"2025060408313332600_iyaf054-B36","doi-asserted-by":"publisher","first-page":"e1005003","DOI":"10.1371\/journal.pgen.1005003","article-title":"The Bicoid class homeodomain factors ceh-36\/OTX and unc-30\/PITX cooperate in C. elegans embryonic progenitor cells to regulate robust development","volume":"11","author":"Walton","year":"2015","journal-title":"PLoS Genet"},{"issue":"1","key":"2025060408313332600_iyaf054-B37","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.cell.2013.02.050","article-title":"Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response","volume":"153","author":"Watson","year":"2013","journal-title":"Cell"},{"issue":"4","key":"2025060408313332600_iyaf054-B38","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/j.cell.2014.01.047","article-title":"Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits","volume":"156","author":"Watson","year":"2014","journal-title":"Cell"},{"key":"2025060408313332600_iyaf054-B39","doi-asserted-by":"publisher","first-page":"e17670","DOI":"10.7554\/eLife.17670","article-title":"Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans","volume":"5","author":"Watson","year":"2016","journal-title":"Elife"},{"issue":"38","key":"2025060408313332600_iyaf054-B40","doi-asserted-by":"publisher","first-page":"15132","DOI":"10.1073\/pnas.0707001104","article-title":"Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching","volume":"104","author":"Wu","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"2025060408313332600_iyaf054-B41","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.tig.2014.07.010","article-title":"Worms, bacteria, and micronutrients: an elegant model of our diet","volume":"30","author":"Yilmaz","year":"2014","journal-title":"Trends Genet"},{"issue":"5","key":"2025060408313332600_iyaf054-B42","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.devcel.2009.03.008","article-title":"The polycomb complex protein mes-2\/E(z) promotes the transition from developmental plasticity to differentiation in C. elegans embryos","volume":"16","author":"Yuzyuk","year":"2009","journal-title":"Dev Cell"}],"container-title":["GENETICS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/advance-article-pdf\/doi\/10.1093\/genetics\/iyaf054\/62711145\/iyaf054.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/230\/2\/iyaf054\/62711145\/iyaf054.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/230\/2\/iyaf054\/62711145\/iyaf054.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T12:31:37Z","timestamp":1749040297000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/doi\/10.1093\/genetics\/iyaf054\/8093452"}},"subtitle":[],"editor":[{"given":"M","family":"Boxem","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,3,25]]},"published-print":{"date-parts":[[2025,6,4]]}},"URL":"https:\/\/doi.org\/10.1093\/genetics\/iyaf054","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,3,25]]},"article-number":"iyaf054"}}