{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:08:54Z","timestamp":1790046534817,"version":"4.0.1"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001255","name":"Lister Institute of Preventive Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001255","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with the hypomorphic\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt<\/jats:italic>\n                    <\/jats:sup>\n                    mutation. MTRR is necessary for methyl group utilisation from folate metabolism, and the\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt<\/jats:italic>\n                    <\/jats:sup>\n                    allele disrupts this process. We show that the spectrum of phenotypes previously observed in\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt\/gt<\/jats:italic>\n                    <\/jats:sup>\n                    conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes. Notably, we report misalignment of some\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt<\/jats:italic>\n                    <\/jats:sup>\n                    conceptuses within their implantation sites from E6.5. The degree of misorientation occurs across a continuum, with the most severe form visible upon gross dissection. Additionally, some\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt\/gt<\/jats:italic>\n                    <\/jats:sup>\n                    conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Skewed growth likely influences embryo development since developmental delay and heart malformations (but not defects in neural tube closure or trophoblast differentiation) associate with severe misalignment of\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt\/gt<\/jats:italic>\n                    <\/jats:sup>\n                    conceptuses. Typically, the uterus is thought to guide conceptus orientation. To investigate a uterine effect of the\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt<\/jats:italic>\n                    <\/jats:sup>\n                    allele, we manipulate the maternal\n                    <jats:italic>Mtrr<\/jats:italic>\n                    genotype. Misaligned conceptuses were observed in litters of\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/+<\/jats:italic>\n                    <\/jats:sup>\n                    ,\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/gt<\/jats:italic>\n                    <\/jats:sup>\n                    , and\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt\/gt<\/jats:italic>\n                    <\/jats:sup>\n                    mothers. While progesterone and\/or BMP2 signalling might be disrupted, normal decidual morphology, patterning, and blood perfusion are evident at E6.5 regardless of conceptus orientation. These observations argue against a post-implantation uterine defect as a cause of conceptus misalignment. Since litters of\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/+<\/jats:italic>\n                    <\/jats:sup>\n                    mothers display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the\n                    <jats:italic>Mtrr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>gt<\/jats:italic>\n                    <\/jats:sup>\n                    model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe conceptus skewing associates with the\n                    <jats:italic>Mtrr<\/jats:italic>\n                    genotype of either maternal grandparent. Moreover, the presence of conceptus skewing after embryo transfer into a control uterus indicates that misalignment is independent of the peri- and\/or post-implantation uterus and instead is likely attributed to an embryonic mechanism that is epigenetically inherited. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. This study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2021.723978","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T02:35:15Z","timestamp":1639103715000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Disruption of Folate Metabolism Causes Poor Alignment and Spacing of Mouse Conceptuses for Multiple Generations"],"prefix":"10.3389","volume":"9","author":[{"given":"Amy L.","family":"Wilkinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Menelaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Rakoczy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu S.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica D.","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1242\/dev.122.6.1723","article-title":"Expression and Function of Matrix Metalloproteinases and Their Inhibitors at the Maternal-Embryonic Boundary During Mouse Embryo Implantation","volume":"122","author":"Alexander","year":"1996","journal-title":"Development"},{"key":"B2","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/s1097-2765(00)80209-9","article-title":"PPAR\u03b3 Is Required for Placental, Cardiac, and Adipose Tissue Development","volume":"4","author":"Barak","year":"1999","journal-title":"Mol. Cel."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1038\/s41588-021-00898-9","article-title":"Variably Methylated Retrotransposons Are Refractory to a Range of Environmental Perturbations","volume":"53","author":"Bertozzi","year":"2021","journal-title":"Nat. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3714","DOI":"10.1038\/s41467-021-24036-5","article-title":"Defective Folate Metabolism Causes Germline Epigenetic Instability and Distinguishes Hira as a Phenotype Inheritance Biomarker","volume":"12","author":"Blake","year":"2021","journal-title":"Nat. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.cbpa.2016.06.008","article-title":"Unravelling the Complex Mechanisms of Transgenerational Epigenetic Inheritance","volume":"33","author":"Blake","year":"2016","journal-title":"Curr. Opin. Chem. Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3290","DOI":"10.1073\/pnas.94.7.3290","article-title":"Folate Deficiency Causes Uracil Misincorporation into Human DNA and Chromosome Breakage: Implications for Cancer and Neuronal Damage","volume":"94","author":"Blount","year":"1997","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1000061","DOI":"10.1371\/journal.pmed.1000061","article-title":"Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study","volume":"6","author":"Bukowski","year":"2009","journal-title":"Plos Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1002\/tera.10040","article-title":"Investigation of the Effects of Folate Deficiency on Embryonic Development Through the Establishment of a Folate Deficient Mouse Model","volume":"65","author":"Burgoon","year":"2002","journal-title":"Teratology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.1093\/hmg\/ddn262","article-title":"Gene-environment Interactions in the Causation of Neural Tube Defects: Folate Deficiency Increases Susceptibility Conferred by Loss of Pax3 Function","volume":"17","author":"Burren","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.celrep.2014.06.027","article-title":"Appropriate Crypt Formation in the Uterus for Embryo Homing and Implantation Requires Wnt5a-ROR Signaling","volume":"8","author":"Cha","year":"2014","journal-title":"Cel. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1677\/jme.0.0160107","article-title":"Developmental Expression of the Cyclo-Oxygenase-1 and Cyclo-Oxygenase-2 Genes in the Peri-Implantation Mouse Uterus and Their Differential Regulation by the Blastocyst and Ovarian Steroids","volume":"16","author":"Chakraborty","year":"1996","journal-title":"J. Mol. Endocrinol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1126\/science.aad7977","article-title":"Sperm tsRNAs Contribute to Intergenerational Inheritance of an Acquired Metabolic Disorder","volume":"351","author":"Chen","year":"2016","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1016\/j.mam.2012.07.017","article-title":"Navigating the Site for Embryo Implantation: Biomechanical and Molecular Regulation of Intrauterine Embryo Distribution","volume":"34","author":"Chen","year":"2013","journal-title":"Mol. Aspects Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.placenta.2012.02.005","article-title":"Spatial and Temporal Expression of Folate-Related Transporters and Metabolic Enzymes During Mouse Placental Development","volume":"33","author":"Cherukad","year":"2012","journal-title":"Placenta"},{"key":"B15","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/j.1749-6632.2003.tb03212.x","article-title":"Chorioallantoic Morphogenesis and Formation of the Placental Villous Tree","volume":"995","author":"Cross","year":"2003","journal-title":"Ann. N. Y Acad. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1126\/science.7985020","article-title":"Implantation and the Placenta: Key Pieces of the Development Puzzle","volume":"266","author":"Cross","year":"1994","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1016\/j.devcel.2011.09.010","article-title":"Conditional Deletion of Msx Homeobox Genes in the Uterus Inhibits Blastocyst Implantation by Altering Uterine Receptivity","volume":"21","author":"Daikoku","year":"2011","journal-title":"Develop. Cel."},{"key":"B18","doi-asserted-by":"publisher","first-page":"13927","DOI":"10.1073\/pnas.1902688116","article-title":"High-resolution Contrast-Enhanced microCT Reveals the True Three-Dimensional Morphology of the Murine Placenta","volume":"116","author":"De Clercq","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","article-title":"One-Carbon Metabolism in Health and Disease","volume":"25","author":"Ducker","year":"2017","journal-title":"Cel. Metab."},{"key":"B20","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.ymgme.2007.02.001","article-title":"Metabolic Derangement of Methionine and Folate Metabolism in Mice Deficient in Methionine Synthase Reductase","volume":"91","author":"Elmore","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"dev193490","DOI":"10.1242\/dev.193490","article-title":"Mechanical and Signaling Mechanisms that Guide Pre-implantation Embryo Movement","volume":"147","author":"Flores","year":"2020","journal-title":"Development"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.3390\/ijms21051885","article-title":"Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems","volume":"21","author":"Fujiwara","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"276.e1","DOI":"10.1016\/j.ajog.2008.06.020","article-title":"One-carbon Metabolism Enzyme Polymorphisms and Uteroplacental Insufficiency","volume":"199","author":"Furness","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1093\/humrep\/des187","article-title":"Effect of Folate Deficiency on Promoter Methylation and Gene Expression of Esr1, Cdh1 and Pgr, and its Influence on Endometrial Receptivity and Embryo Implantation","volume":"27","author":"Gao","year":"2012","journal-title":"Hum. Reprod."},{"key":"B25","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1002\/bdra.20453","article-title":"Embryonic Development in the Reduced Folate Carrier Knockout Mouse Is Modulated by Maternal Folate Supplementation","volume":"82","author":"Gelineau-van Waes","year":"2008","journal-title":"Birth Defect Res. A."},{"key":"B26","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1093\/molehr\/gav045","article-title":"Folate Deficiency Impairs Decidualization and Alters Methylation Patterns of the Genome in Mice","volume":"21","author":"Geng","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"B27","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.ydbio.2017.01.015","article-title":"Differential Wnt Signaling Activity Limits Epithelial Gland Development to the Anti-mesometrial Side of the Mouse Uterus","volume":"423","author":"Goad","year":"2017","journal-title":"Develop. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1093\/jn\/122.4.888","article-title":"Folate Deficiency Alone Does Not Produce Neural Tube Defects in Mice","volume":"122","author":"Heid","year":"1992","journal-title":"J. Nutr."},{"key":"B29","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/s1043-2760(01)00375-7","article-title":"Genes Governing Placental Development","volume":"12","author":"Hemberger","year":"2001","journal-title":"Trends Endocrinol. Metab."},{"key":"B30","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/aja.1000980306","article-title":"A Description of 34 Human Ova Within the First 17 Days of Development","volume":"98","author":"Hertig","year":"1956","journal-title":"Am. J. Anat."},{"key":"B31","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.pbiomolbio.2012.08.014","article-title":"Epigenetic Inheritance and Plasticity: The Responsive Germline","volume":"111","author":"Jablonka","year":"2013","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1016\/j.fertnstert.2013.01.108","article-title":"Association of Methionine Synthase and Thymidylate Synthase Genetic Polymorphisms with Idiopathic Recurrent Pregnancy Loss","volume":"99","author":"Kim","year":"2013","journal-title":"Fertil. Sterility"},{"key":"B33","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1242\/dev.17.3.527","article-title":"On the Orientation of the Implanting Blastocyst","volume":"17","author":"Kirby","year":"1967","journal-title":"J. Embryol. Exp. Morphol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4067","DOI":"10.1073\/pnas.91.9.4067","article-title":"Apoptosis Mediates and Thymidine Prevents Erythroblast Destruction in Folate Deficiency Anemia","volume":"91","author":"Koury","year":"1994","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"S115","DOI":"10.1079\/bjn2000303","article-title":"Importance of Folate in Human Nutrition","volume":"85","author":"Krishnaswamy","year":"2001","journal-title":"Br. J. Nutr."},{"key":"B36","doi-asserted-by":"publisher","first-page":"5468","DOI":"10.1128\/MCB.00342-07","article-title":"Bmp2 Is Critical for the Murine Uterine Decidual Response","volume":"27","author":"Lee","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1210\/mend.13.6.0284","article-title":"Hoxa-10Regulates Uterine Stromal Cell Responsiveness to Progesterone During Implantation and Decidualization in the Mouse","volume":"13","author":"Lim","year":"1999","journal-title":"Mol. Endocrinol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.devcel.2021.01.014","article-title":"Histone H3 Lysine 4 Trimethylation in Sperm Is Transmitted to the Embryo and Associated with Diet-Induced Phenotypes in the Offspring","volume":"56","author":"Lismer","year":"2021","journal-title":"Develop. Cel."},{"key":"B39","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B40","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.placenta.2020.10.036","article-title":"Fused Placentas: Till Birth Do Us Part","volume":"103","author":"Lopez-Tello","year":"2021","journal-title":"Placenta"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e78446","DOI":"10.1371\/journal.pone.0078446","article-title":"Excessive Intrauterine Fluid Cause Aberrant Implantation and Pregnancy Outcome in Mice","volume":"8","author":"Lu","year":"2013","journal-title":"PLoS One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1101\/gad.9.18.2266","article-title":"Mice Lacking Progesterone Receptor Exhibit Pleiotropic Reproductive Abnormalities","volume":"9","author":"Lydon","year":"1995","journal-title":"Genes Dev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.ydbio.2009.04.036","article-title":"Active Cell Movements Coupled to Positional Induction Are Involved in Lineage Segregation in the Mouse Blastocyst","volume":"331","author":"Meilhac","year":"2009","journal-title":"Develop. Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"6364","DOI":"10.1073\/pnas.0915063107","article-title":"Origin and Formation of the First Two Distinct Cell Types of the Inner Cell Mass in the Mouse Embryo","volume":"107","author":"Morris","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/0140-6736(91)90133-a","article-title":"Prevention of Neural Tube Defects: Results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group","volume":"338","year":"1991","journal-title":"Lancet"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1111\/jog.12392","article-title":"Regulation of Decidualization and Angiogenesis in the Human Endometrium: Mini Review","volume":"40","author":"Okada","year":"2014","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"622","DOI":"10.3389\/fphys.2019.00622","article-title":"Secondary Placental Defects in Cxadr Mutant Mice","volume":"10","author":"Outhwaite","year":"2019","journal-title":"Front. Physiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.cell.2013.09.002","article-title":"Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects on Development","volume":"155","author":"Padmanabhan","year":"2013","journal-title":"Cell"},{"key":"B49","doi-asserted-by":"publisher","first-page":"4341","DOI":"10.1113\/JP276419","article-title":"Abnormal Folate Metabolism Causes Age\u2010, Sex\u2010 and Parent\u2010of\u2010origin\u2010specific Haematological Defects in Mice","volume":"596","author":"Padmanabhan","year":"2018","journal-title":"J. Physiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"dvx014","DOI":"10.1093\/eep\/dvx014","article-title":"Multigenerational Analysis of Sex-specific Phenotypic Differences at Midgestation Caused by Abnormal Folate Metabolism","volume":"3","author":"Padmanabhan","year":"2017","journal-title":"Environ. Epigenet."},{"key":"B51","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nature26002","article-title":"Placentation Defects Are Highly Prevalent in Embryonic Lethal Mouse Mutants","volume":"555","author":"Perez-Garcia","year":"2018","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1002\/bdra.20575","article-title":"Methylenetetrahydrofolate Reductase Deficiency and Low Dietary Folate Increase Embryonic Delay and Placental Abnormalities in Mice","volume":"85","author":"Pickell","year":"2009","journal-title":"Birth Defect Res. A: Clin. Mol. Teratology"},{"key":"B53","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/13861","article-title":"Mice Lacking the Folic Acid-Binding Protein Folbp1 Are Defective in Early Embryonic Development","volume":"23","author":"Piedrahita","year":"1999","journal-title":"Nat. Genet."},{"key":"B54","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1172\/JCI2299110.1172\/jci200422991","article-title":"Trophoblast Differentiation During Embryo Implantation and Formation of the Maternal-Fetal Interface","volume":"114","author":"Red-Horse","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1016\/j.fertnstert.2006.05.052","article-title":"Methylenetetrahydrofolate Reductase C677T Polymorphism and the Risk of Unexplained Recurrent Pregnancy Loss: A Meta-Analysis","volume":"86","author":"Ren","year":"2006","journal-title":"Fertil. Sterility"},{"key":"B56","doi-asserted-by":"publisher","first-page":"4895","DOI":"10.1182\/blood-2010-04-279653","article-title":"A Mouse Model of Hereditary Folate Malabsorption: Deletion of the PCFT Gene Leads to Systemic Folate Deficiency","volume":"117","author":"Salojin","year":"2011","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1146\/annurev.nu.05.070185.000555","article-title":"Vitamin B12-Folate Interrelationships","volume":"5","author":"Shane","year":"1985","journal-title":"Annu. Rev. Nutr."},{"key":"B58","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1126\/science.aad6780","article-title":"Biogenesis and Function of tRNA Fragments During Sperm Maturation and Fertilization in Mammals","volume":"351","author":"Sharma","year":"2016","journal-title":"Science"},{"key":"B59","doi-asserted-by":"publisher","first-page":"4558","DOI":"10.1242\/dev.115659","article-title":"Celsr1 Is Required for the Generation of Polarity at Multiple Levels of the Mouse Oviduct","volume":"141","author":"Shi","year":"2014","journal-title":"Development"},{"key":"B60","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ydbio.2005.05.010","article-title":"Determinants of Trophoblast Lineage and Cell Subtype Specification in the Mouse Placenta","volume":"284","author":"Simmons","year":"2005","journal-title":"Develop. Biol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1242\/dev.020099","article-title":"Early Patterning of the Chorion Leads to the Trilaminar Trophoblast Cell Structure in the Placental Labyrinth","volume":"135","author":"Simmons","year":"2008","journal-title":"Development"},{"key":"B62","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1242\/dev.89.1.15","article-title":"Embryonic axis Orientation in the Mouse and its Correlation with Blastocyst Relationships to the Uterus","volume":"89","author":"Smith","year":"1985","journal-title":"J. Embryol. Exp. Morphol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.placenta.2015.12.017","article-title":"Identification of Suitable Reference Genes in the Mouse Placenta","volume":"39","author":"Solano","year":"2016","journal-title":"Placenta"},{"key":"B64","doi-asserted-by":"publisher","first-page":"100580","DOI":"10.1016\/j.ymgmr.2020.100580","article-title":"Mtrr Hypomorphic Mutation Alters Liver Morphology, Metabolism and Fuel Storage in Mice","volume":"23","author":"Sowton","year":"2020","journal-title":"Mol. Genet. Metab. Rep."},{"key":"B65","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1111\/j.1753-4887.2004.tb00070.x","article-title":"Physiology of Folate and Vitamin B12in Health and Disease","volume":"62","author":"Stover","year":"2004","journal-title":"Nutr. Rev."},{"key":"B66","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1128\/MCB.21.4.1058-1065.2001","article-title":"Targeted Disruption of the Methionine Synthase Gene in Mice","volume":"21","author":"Swanson","year":"2001","journal-title":"Mol. Cel. Biol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s13293-017-0154-6","article-title":"Genetic Sex Determination of Mice by Simplex PCR","volume":"8","author":"Tunster","year":"2017","journal-title":"Biol. Sex. Differ."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1095\/biolreprod.103.017608","article-title":"Possible Expansion of \"Window of Implantation\" in Pseudopregnant Mice: Time of Implantation of Embryos at Different Stages of Development Transferred into the Same Recipient","volume":"69","author":"Ueda","year":"2003","journal-title":"Biol. Reprod."},{"key":"B69","doi-asserted-by":"publisher","first-page":"e1367","DOI":"10.1097\/MD.0000000000001367","article-title":"Analysis of MTR and MTRR Polymorphisms for Neural Tube Defects Risk Association","volume":"94","author":"Wang","year":"2015","journal-title":"Medicine (Baltimore)"},{"key":"B70","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1152\/physiol.00001.2005","article-title":"Development of Structures and Transport Functions in the Mouse Placenta","volume":"20","author":"Watson","year":"2005","journal-title":"Physiology"},{"key":"B71","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1038\/ng.3554","article-title":"Fat Eggs Shape Offspring Health","volume":"48","author":"Watson","year":"2016","journal-title":"Nat. Genet."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1503\/cmaj.080859","article-title":"Maternal Exposure to Folic Acid Antagonists and Placenta-Mediated Adverse Pregnancy Outcomes","volume":"179","author":"Wen","year":"2008","journal-title":"Can. Med. Assoc. J."},{"key":"B73","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.mce.2011.10.028","article-title":"The Progesterone Receptor Regulates Implantation, Decidualization, and Glandular Development via a Complex Paracrine Signaling Network","volume":"357","author":"Wetendorf","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1095\/biolreprod.113.111690","article-title":"Decidual Angiogenesis and Placental Orientation Are Altered in Mice Heterozygous for a Dominant Loss-Of-Function Gja1 (Connexin43) Mutation1","volume":"89","author":"Winterhager","year":"2013","journal-title":"Biol. Reprod."},{"key":"B75","doi-asserted-by":"publisher","first-page":"9476","DOI":"10.1073\/pnas.0603694103","article-title":"Human Methionine Synthase Reductase Is a Molecular Chaperone for Human Methionine Synthase","volume":"103","author":"Yamada","year":"2006","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B76","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: A Tool to Design Target-specific Primers for Polymerase Chain Reaction","volume":"13","author":"Ye","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"B77","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/cr.2014.82","article-title":"Uterine Rbpj Is Required for Embryonic-Uterine Orientation and Decidual Remodeling via Notch Pathway-independent and -dependent Mechanisms","volume":"24","author":"Zhang","year":"2014","journal-title":"Cell Res."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.723978\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T02:35:18Z","timestamp":1639103718000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.723978\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":77,"alternative-id":["10.3389\/fcell.2021.723978"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.723978","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.11.448112","asserted-by":"object"}]},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,10]]},"article-number":"723978"}}