{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:05:23Z","timestamp":1790046323691,"version":"4.0.1"},"reference-count":67,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2018,8,15]],"date-time":"2018-08-15T00:00:00Z","timestamp":1534291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004117","name":"A.G. 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Megaloblastic anaemia is a type of macrocytic anaemia whereby erythrocytes are enlarged and fewer in number. Folate metabolism is required for thymidine synthesis and one\u2010carbon metabolism, though its specific role in erythropoiesis is not well understood. Methionine synthase reductase (MTRR) is a key enzyme necessary for the progression of folate metabolism since knocking down the <jats:italic>Mtrr<\/jats:italic> gene in mice results in hyperhomocysteinaemia and global DNA hypomethylation. We demonstrate here that abnormal folate metabolism in mice caused by <jats:italic>Mtrr<jats:sup>gt\/gt<\/jats:sup><\/jats:italic> homozygosity leads to haematopoietic phenotypes that are sex and age dependent. Specifically, <jats:italic>Mtrr<jats:sup>gt\/gt<\/jats:sup><\/jats:italic> female mice displayed macrocytic anaemia, which might be due to defective erythroid differentiation at the exclusion of haemolysis. This was associated with increased renal <jats:italic>Epo<\/jats:italic> mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis. In contrast, the male response differed since <jats:italic>Mtrr<jats:sup>gt\/gt<\/jats:sup><\/jats:italic> male mice were not anaemic but did display erythrocytic macrocytosis and lymphopenia. Regardless of sex, these phenotypes were late onset. Remarkably, we also show that when either parent carries an <jats:italic>Mtrr<jats:sup>gt<\/jats:sup><\/jats:italic> allele, a haematological defect results in their adult wildtype daughters. However, the specific phenotype was dependent upon the sex of the parent. For instance, wildtype daughters of <jats:italic>Mtrr<jats:sup>+\/gt<\/jats:sup><\/jats:italic> females displayed normocytic anaemia. In contrast, wildtype daughters of <jats:italic>Mtrr<jats:sup>+\/gt<\/jats:sup><\/jats:italic> males exhibited erythrocytic microcytosis not associated with anaemia. Therefore, abnormal folate metabolism affects adult haematopoiesis in an age\u2010, sex\u2010 and parent\u2010specific manner.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276419","type":"journal-article","created":{"date-parts":[[2018,7,19]],"date-time":"2018-07-19T11:17:29Z","timestamp":1531999049000},"page":"4341-4360","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Abnormal folate metabolism causes age\u2010, sex\u2010 and parent\u2010of\u2010origin\u2010specific haematological defects in mice"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1253-2162","authenticated-orcid":false,"given":"Nisha","family":"Padmanabhan","sequence":"first","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge  Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Menelaou","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge  Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge  Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina E. 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