{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:10:18Z","timestamp":1791144618153,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2006,8,24]],"date-time":"2006-08-24T00:00:00Z","timestamp":1156377600000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2006,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND:<\/jats:bold>Closure of the cranial neural tube during embryogenesis is a crucial process in development of the brain. Failure of this event results in the severe neural tube defect (NTD) exencephaly, the developmental forerunner of anencephaly.<jats:bold>METHODS:<\/jats:bold>The requirement for methylation cycle function in cranial neural tube closure was tested by treatment of cultured mouse embryos with cycloleucine or ethionine, inhibitors of methionine adenosyl transferase. Embryonic phenotypes were investigated by histological analysis, and immunostaining was performed for markers of proliferation and apoptosis. Methylation cycle intermediates s\u2010adenosylmethionine and s\u2010adenosylhomocysteine were also quantitated by tandem mass spectrometry.<jats:bold>RESULTS:<\/jats:bold>Ethionine and cycloleucine treatments significantly reduced the ratio of abundance of s\u2010adenosylmethionine to s\u2010adenosylhomocysteine and are, therefore, predicted to suppress the methylation cycle. Exposure to these inhibitors during the period of cranial neurulation caused a high incidence of exencephaly, in the absence of generalized toxicity, growth retardation, or developmental delay. Reduced neuroepithelial thickness and reduced density of cranial mesenchyme were detected in ethionine\u2010treated but not cycloleucine\u2010treated embryos that developed exencephaly. Reduced mesenchymal density is a potential cause of ethionine\u2010induced exencephaly, although we could not detect a causative alteration in proliferation or apoptosis prior to failure of neural tube closure.<jats:bold>CONCLUSIONS:<\/jats:bold>Adequate functioning of the methylation cycle is essential for cranial neural tube closure in the mouse, suggesting that suppression of the methylation cycle could also increase the risk of human NTDs. We hypothesize that inhibition of the methylation cycle causes NTDs due to disruption of crucial reactions involving methylation of DNA, proteins or other biomolecules. Birth Defects Research (Part A) 76:544\u2013552, 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdra.20286","type":"journal-article","created":{"date-parts":[[2006,8,24]],"date-time":"2006-08-24T22:49:45Z","timestamp":1156459785000},"page":"544-552","source":"Crossref","is-referenced-by-count":86,"title":["Integrity of the methylation cycle is essential for mammalian neural tube closure"],"prefix":"10.1002","volume":"76","author":[{"given":"Louisa P.E.","family":"Dunlevy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie A.","family":"Burren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyn S.","family":"Chitty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Copp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D.E.","family":"Greene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,8,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devbrainres.2005.06.002"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2006.07.012"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/131.11.2811"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/oso\/9780199630882.003.0002","volume-title":"Postimplantation mammalian embryos: a practical approach","author":"Cockroft DL","year":"1990"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/119.11.1716"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0301-0082(90)90037-H"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(00)89008-3"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1181"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2005.00476.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.20037"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00014300"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203607200"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-002-0284-3"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30051"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.6.993"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0890-6238(00)00093-9"},{"key":"e_1_2_6_18_1","first-page":"703","article-title":"Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects","volume":"86","author":"Kirke PN","year":"1993","journal-title":"Q J Med"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)64402-9"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.3.283"},{"key":"e_1_2_6_21_1","first-page":"547","article-title":"An open cephalic neural tube reproducibly induced by cytochalasin D in rat embryos in vitro","volume":"11","author":"Matsuda M","year":"1994","journal-title":"Zool Sci"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2980415"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.2.543"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1092260316"},{"key":"e_1_2_6_25_1","first-page":"37","article-title":"Regional differences in mesenchymal cell morphology and glycosaminoglycans in early neural\u2010fold stage rat embryos","volume":"46","author":"Morriss GM","year":"1978","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_6_26_1","first-page":"225","article-title":"Growth and development of pattern in the cranial neural epithelium of rat embryos during neurulation","volume":"65","author":"Morriss\u2010Kay GM","year":"1981","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81656-6"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.26.15227"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0029665199000580"},{"key":"e_1_2_6_30_1","first-page":"167","article-title":"Calcium and neurulation in mammalian embryos. 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