{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:42:53Z","timestamp":1788219773797,"version":"build-2803163510"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T00:00:00Z","timestamp":1448236800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T00:00:00Z","timestamp":1448236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies.<\/jats:p>","DOI":"10.1038\/srep16917","type":"journal-article","created":{"date-parts":[[2015,11,23]],"date-time":"2015-11-23T10:41:29Z","timestamp":1448275289000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Novel Mode of Defective Neural Tube Closure in the Non-Obese Diabetic (NOD) Mouse Strain"],"prefix":"10.1038","volume":"5","author":[{"given":"J. Michael","family":"Salbaum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kruger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacalyn","family":"MacGowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils J.","family":"Herion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Burk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kappen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,23]]},"reference":[{"key":"BFsrep16917_CR1","doi-asserted-by":"publisher","first-page":"1222002","DOI":"10.1126\/science.1222002","volume":"339","author":"JB Wallingford","year":"2013","unstructured":"Wallingford, J. B., Niswander, L. A., Shaw, G. M. & Finnell, R. H. The continuing challenge of understanding, preventing and treating neural tube defects. Science 339, 1222002, doi: 10.1126\/science.1222002 (2013).","journal-title":"Science"},{"key":"BFsrep16917_CR2","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/S1474-4422(13)70110-8","volume":"12","author":"AJ Copp","year":"2013","unstructured":"Copp, A. J., Stanier, P. & Greene, N. D. Neural tube defects: recent advances, unsolved questions and controversies. Lancet Neurol 12, 799\u2013810, doi: 10.1016\/S1474-4422(13)70110-8 (2013).","journal-title":"Lancet Neurol"},{"key":"BFsrep16917_CR3","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1002\/bdra.20676","volume":"88","author":"MJ Harris","year":"2010","unstructured":"Harris, M. J. & Juriloff, D. M. An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res A Clin Mol Teratol 88, 653\u2013669, doi: 10.1002\/bdra.20676 (2010).","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"BFsrep16917_CR4","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1002\/bdra.20680","volume":"88","author":"JM Salbaum","year":"2010","unstructured":"Salbaum, J. M. & Kappen, C. Neural tube defect genes and maternal diabetes during pregnancy. Birth Defects Res A Clin Mol Teratol 88, 601\u2013611, doi: 10.1002\/bdra.20680 (2010).","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"BFsrep16917_CR5","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/1471-2350-13-62","volume":"13","author":"F Pangilinan","year":"2012","unstructured":"Pangilinan, F. et al. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects. BMC Med Genet 13, 62, doi: 10.1186\/1471-2350-13-62 (2012).","journal-title":"BMC Med Genet"},{"key":"BFsrep16917_CR6","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1136\/adc.51.12.944","volume":"51","author":"RW Smithells","year":"1976","unstructured":"Smithells, R. W., Sheppard, S. & Schorah, C. J. Vitamin dificiencies and neural tube defects. Arch Dis Child 51, 944\u2013950 (1976).","journal-title":"Arch Dis Child"},{"key":"BFsrep16917_CR7","doi-asserted-by":"publisher","first-page":"292","DOI":"10.2337\/diab.28.4.292","volume":"28","author":"JL Mills","year":"1979","unstructured":"Mills, J. L., Baker, L. & Goldman, A. S. Malformations in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment. Diabetes 28, 292\u2013293 (1979).","journal-title":"Diabetes"},{"key":"BFsrep16917_CR8","first-page":"73","volume":"7","author":"J Kucera","year":"1971","unstructured":"Kucera, J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7, 73\u201382 (1971).","journal-title":"J Reprod Med"},{"key":"BFsrep16917_CR9","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1002\/ajmg.1320510206","volume":"51","author":"ML Martinez-Frias","year":"1994","unstructured":"Martinez-Frias, M. L. Epidemiological analysis of outcomes of pregnancy in diabetic mothers: identification of the most characteristic and most frequent congenital anomalies. Am J Med Genet 51, 108\u2013113, doi: 10.1002\/ajmg.1320510206 (1994).","journal-title":"Am J Med Genet"},{"key":"BFsrep16917_CR10","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1097\/00008480-199408000-00023","volume":"6","author":"MP Goto","year":"1994","unstructured":"Goto, M. P. & Goldman, A. S. Diabetic embryopathy. Curr Opin Pediatr 6, 486\u2013491 (1994).","journal-title":"Curr Opin Pediatr"},{"key":"BFsrep16917_CR11","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1002\/tera.10060","volume":"66","author":"LJ Williams","year":"2002","unstructured":"Williams, L. J. et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology 66, 33\u201339, doi: 10.1002\/tera.10060 (2002).","journal-title":"Teratology"},{"key":"BFsrep16917_CR12","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1111\/j.1442-2042.2008.02163.x","volume":"16","author":"A Kondo","year":"2009","unstructured":"Kondo, A., Kamihira, O. & Ozawa, H. Neural tube defects: prevalence, etiology and prevention. Int J Urol 16, 49\u201357, doi: 10.1111\/j.1442-2042.2008.02163.x (2009).","journal-title":"Int J Urol"},{"key":"BFsrep16917_CR13","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1096\/fasebj.3.11.2673897","volume":"3","author":"EH Leiter","year":"1989","unstructured":"Leiter, E. H. The genetics of diabetes susceptibility in mice. Faseb J 3, 2231\u20132241 (1989).","journal-title":"Faseb J"},{"key":"BFsrep16917_CR14","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s11892-005-0042-z","volume":"5","author":"EH Leiter","year":"2005","unstructured":"Leiter, E. H. Nonobese diabetic mice and the genetics of diabetes susceptibility. Curr Diab Rep 5, 141\u2013148 (2005).","journal-title":"Curr Diab Rep"},{"key":"BFsrep16917_CR15","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.2337\/diab.40.10.1245","volume":"40","author":"H Otani","year":"1991","unstructured":"Otani, H., Tanaka, O., Tatewaki, R., Naora, H. & Yoneyama, T. Diabetic environment and genetic predisposition as causes of congenital malformations in NOD mouse embryos. Diabetes 40, 1245\u20131250 (1991).","journal-title":"Diabetes"},{"key":"BFsrep16917_CR16","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1002\/tera.1420440113","volume":"44","author":"M Morishima","year":"1991","unstructured":"Morishima, M., Ando, M. & Takao, A. Visceroatrial heterotaxy syndrome in the NOD mouse with special reference to atrial situs. Teratology 44, 91\u2013100, doi: 10.1002\/tera.1420440113 (1991).","journal-title":"Teratology"},{"key":"BFsrep16917_CR17","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1002\/(SICI)1096-9926(199610)54:4<183::AID-TERA2>3.0.CO;2-2","volume":"54","author":"M Morishima","year":"1996","unstructured":"Morishima, M., Yasui, H., Ando, M., Nakazawa, M. & Takao, A. Influence of genetic and maternal diabetes in the pathogenesis of visceroatrial heterotaxy in mice. Teratology 54, 183\u2013190, doi: 10.1002\/(SICI)1096-9926(199610)54:4&lt;183::AID-TERA2&gt;3.0.CO;2-2 (1996).","journal-title":"Teratology"},{"key":"BFsrep16917_CR18","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1186\/1471-2164-10-274","volume":"10","author":"G Pavlinkova","year":"2009","unstructured":"Pavlinkova, G., Salbaum, J. M. & Kappen, C. Maternal diabetes alters transcriptional programs in the developing embryo. BMC Genomics 10, 274, doi: 10.1186\/1471-2164-10-274 (2009).","journal-title":"BMC Genomics"},{"key":"BFsrep16917_CR19","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.reprotox.2010.09.002","volume":"31","author":"C Kappen","year":"2011","unstructured":"Kappen, C., Kruger, C., MacGowan, J. & Salbaum, J. M. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy. Reprod Toxicol 31, 41\u201349, doi: 10.1016\/j.reprotox.2010.09.002 (2011).","journal-title":"Reprod Toxicol"},{"key":"BFsrep16917_CR20","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1038\/ncb890","volume":"4","author":"S Beck","year":"2002","unstructured":"Beck, S. et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nat Cell Biol 4, 981\u2013985, doi: 10.1038\/ncb890 (2002).","journal-title":"Nat Cell Biol"},{"key":"BFsrep16917_CR21","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1016\/j.cell.2011.07.028","volume":"146","author":"N Ramkumar","year":"2011","unstructured":"Ramkumar, N. & Anderson, K. V. SnapShot: mouse primitive streak. Cell 146, 488\u2013488 e482, doi: 10.1016\/j.cell.2011.07.028 (2011).","journal-title":"Cell"},{"key":"BFsrep16917_CR22","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/j.stem.2009.07.012","volume":"5","author":"A Nishiyama","year":"2009","unstructured":"Nishiyama, A. et al. Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell 5, 420\u2013433, doi: 10.1016\/j.stem.2009.07.012 (2009).","journal-title":"Cell Stem Cell"},{"key":"BFsrep16917_CR23","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/path.4082","volume":"228","author":"AC Nelson","year":"2012","unstructured":"Nelson, A. C. et al. An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma. J Pathol 228, 274\u2013285, doi: 10.1002\/path.4082 (2012).","journal-title":"J Pathol"},{"key":"BFsrep16917_CR24","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/nature09729","volume":"470","author":"T Takemoto","year":"2011","unstructured":"Takemoto, T. et al. Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 470, 394\u2013398, doi: 10.1038\/nature09729 (2011).","journal-title":"Nature"},{"key":"BFsrep16917_CR25","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/343657a0","volume":"343","author":"DG Wilkinson","year":"1990","unstructured":"Wilkinson, D. G., Bhatt, S. & Herrmann, B. G. Expression pattern of the mouse T gene and its role in mesoderm formation. Nature 343, 657\u2013659, doi: 10.1038\/343657a0 (1990).","journal-title":"Nature"},{"key":"BFsrep16917_CR26","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1006\/dbio.1996.0326","volume":"180","author":"DL Chapman","year":"1996","unstructured":"Chapman, D. L., Agulnik, I., Hancock, S., Silver, L. M. & Papaioannou, V. E. Tbx6, a mouse T-Box gene implicated in paraxial mesoderm formation at gastrulation. Dev Biol 180, 534\u2013542, doi: 10.1006\/dbio.1996.0326 (1996).","journal-title":"Dev Biol"},{"key":"BFsrep16917_CR27","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.gde.2008.07.017","volume":"18","author":"FC Wardle","year":"2008","unstructured":"Wardle, F. C. & Papaioannou, V. E. Teasing out T-box targets in early mesoderm. Curr Opin Genet Dev 18, 418\u2013425, doi: 10.1016\/j.gde.2008.07.017 (2008).","journal-title":"Curr Opin Genet Dev"},{"key":"BFsrep16917_CR28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.matbio.2011.04.001","volume":"30","author":"AJ Copp","year":"2011","unstructured":"Copp, A. J. et al. Regional differences in the expression of laminin isoforms during mouse neural tube development. Matrix Biol 30, 301\u2013309, doi: 10.1016\/j.matbio.2011.04.001 (2011).","journal-title":"Matrix Biol"},{"key":"BFsrep16917_CR29","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1006\/excr.2002.5611","volume":"279","author":"K Salmivirta","year":"2002","unstructured":"Salmivirta, K. et al. Binding of mouse nidogen-2 to basement membrane components and cells and its expression in embryonic and adult tissues suggest complementary functions of the two nidogens. Exp Cell Res 279, 188\u2013201 (2002).","journal-title":"Exp Cell Res"},{"key":"BFsrep16917_CR30","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.ydbio.2007.04.031","volume":"308","author":"IT Rebustini","year":"2007","unstructured":"Rebustini, I. T. et al. Laminin alpha5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through beta1 integrin signaling. Dev Biol 308, 15\u201329, doi: 10.1016\/j.ydbio.2007.04.031 (2007).","journal-title":"Dev Biol"},{"key":"BFsrep16917_CR31","doi-asserted-by":"publisher","first-page":"975","DOI":"10.2337\/diab.42.7.975","volume":"42","author":"E Cagliero","year":"1993","unstructured":"Cagliero, E., Forsberg, H., Sala, R., Lorenzi, M. & Eriksson, U. J. Maternal diabetes induces increased expression of extracellular matrix components in rat embryos. Diabetes 42, 975\u2013980 (1993).","journal-title":"Diabetes"},{"key":"BFsrep16917_CR32","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1242\/dev.118.3.829","volume":"118","author":"CA Burdsal","year":"1993","unstructured":"Burdsal, C. A., Damsky, C. H. & Pedersen, R. A. The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak. Development 118, 829\u2013844 (1993).","journal-title":"Development"},{"key":"BFsrep16917_CR33","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.ydbio.2013.05.029","volume":"381","author":"JZ Jin","year":"2013","unstructured":"Jin, J. Z. & Ding, J. Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation. Dev Biol 381, 170\u2013178, doi: 10.1016\/j.ydbio.2013.05.029 (2013).","journal-title":"Dev Biol"},{"key":"BFsrep16917_CR34","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1242\/dev.014357","volume":"135","author":"SJ Arnold","year":"2008","unstructured":"Arnold, S. J., Hofmann, U. K., Bikoff, E. K. & Robertson, E. J. Pivotal roles for eomesodermin during axis formation, epithelium-to-mesenchyme transition and endoderm specification in the mouse. Development 135, 501\u2013511, doi: 10.1242\/dev.014357 (2008).","journal-title":"Development"},{"key":"BFsrep16917_CR35","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1101\/gad.13.14.1834","volume":"13","author":"X Sun","year":"1999","unstructured":"Sun, X., Meyers, E. N., Lewandoski, M. & Martin, G. R. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev 13, 1834\u20131846 (1999).","journal-title":"Genes Dev"},{"key":"BFsrep16917_CR36","doi-asserted-by":"publisher","first-page":"2251","DOI":"10.1242\/dev.004929","volume":"134","author":"Q Guo","year":"2007","unstructured":"Guo, Q. & Li, J. Y. Distinct functions of the major Fgf8 spliceform, Fgf8b, before and during mouse gastrulation. Development 134, 2251\u20132260, doi: 10.1242\/dev.004929 (2007).","journal-title":"Development"},{"key":"BFsrep16917_CR37","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.1101\/gad.8.24.3045","volume":"8","author":"CX Deng","year":"1994","unstructured":"Deng, C. X. et al. Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev 8, 3045\u20133057 (1994).","journal-title":"Genes Dev"},{"key":"BFsrep16917_CR38","doi-asserted-by":"publisher","first-page":"2829","DOI":"10.1242\/dev.124.14.2829","volume":"124","author":"BG Ciruna","year":"1997","unstructured":"Ciruna, B. G., Schwartz, L., Harpal, K., Yamaguchi, T. P. & Rossant, J. Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak. Development 124, 2829\u20132841 (1997).","journal-title":"Development"},{"key":"BFsrep16917_CR39","doi-asserted-by":"publisher","first-page":"2803","DOI":"10.1242\/dev.01137","volume":"131","author":"OG Kelly","year":"2004","unstructured":"Kelly, O. G., Pinson, K. I. & Skarnes, W. C. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 131, 2803\u20132815, doi: 10.1242\/dev.01137 (2004).","journal-title":"Development"},{"key":"BFsrep16917_CR40","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1242\/dev.128.9.1559","volume":"128","author":"Y Xue","year":"2001","unstructured":"Xue, Y. et al. Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK). Development 128, 1559\u20131572 (2001).","journal-title":"Development"},{"key":"BFsrep16917_CR41","doi-asserted-by":"publisher","first-page":"3215","DOI":"10.1242\/dev.127.15.3215","volume":"127","author":"S Kitajima","year":"2000","unstructured":"Kitajima, S., Takagi, A., Inoue, T. & Saga, Y. MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development 127, 3215\u20133226 (2000).","journal-title":"Development"},{"key":"BFsrep16917_CR42","doi-asserted-by":"publisher","first-page":"3597","DOI":"10.1242\/dev.129.15.3597","volume":"129","author":"AH Hart","year":"2002","unstructured":"Hart, A. H. et al. Mixl1 is required for axial mesendoderm morphogenesis and patterning in the murine embryo. Development 129, 3597\u20133608 (2002).","journal-title":"Development"},{"key":"BFsrep16917_CR43","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.ydbio.2012.02.005","volume":"364","author":"J Bloomekatz","year":"2012","unstructured":"Bloomekatz, J., Grego-Bessa, J., Migeotte, I. & Anderson, K. V. Pten regulates collective cell migration during specification of the anterior-posterior axis of the mouse embryo. Dev Biol 364, 192\u2013201, doi: 10.1016\/j.ydbio.2012.02.005 (2012).","journal-title":"Dev Biol"},{"key":"BFsrep16917_CR44","doi-asserted-by":"publisher","first-page":"e1000442","DOI":"10.1371\/journal.pbio.1000442","volume":"8","author":"I Migeotte","year":"2010","unstructured":"Migeotte, I., Omelchenko, T., Hall, A. & Anderson, K. V. Rac1-dependent collective cell migration is required for specification of the anterior-posterior body axis of the mouse. PLoS Biol 8, e1000442, doi: 10.1371\/journal.pbio.1000442 (2010).","journal-title":"PLoS Biol"},{"key":"BFsrep16917_CR45","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.1242\/dev.059766","volume":"138","author":"I Migeotte","year":"2011","unstructured":"Migeotte, I., Grego-Bessa, J. & Anderson, K. V. Rac1 mediates morphogenetic responses to intercellular signals in the gastrulating mouse embryo. Development 138, 3011\u20133020, doi: 10.1242\/dev.059766 (2011).","journal-title":"Development"},{"key":"BFsrep16917_CR46","doi-asserted-by":"publisher","first-page":"3790","DOI":"10.1073\/pnas.96.7.3790","volume":"96","author":"TM Saxton","year":"1999","unstructured":"Saxton, T. M. & Pawson, T. Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp2. Proc Natl Acad Sci USA 96, 3790\u20133795 (1999).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep16917_CR47","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1242\/dev.121.3.877","volume":"121","author":"V Wilson","year":"1995","unstructured":"Wilson, V., Manson, L., Skarnes, W. C. & Beddington, R. S. The T gene is necessary for normal mesodermal morphogenetic cell movements during gastrulation. Development 121, 877\u2013886 (1995).","journal-title":"Development"},{"key":"BFsrep16917_CR48","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1002\/1097-0177(2000)9999:9999<::AID-DVDY1079>3.0.CO;2-Y","volume":"219","author":"SJ Monkley","year":"2000","unstructured":"Monkley, S. J. et al. Disruption of the talin gene arrests mouse development at the gastrulation stage. Dev Dyn 219, 560\u2013574, doi: 10.1002\/1097-0177(2000)9999:9999&lt;::AID-DVDY1079&gt;3.0.CO;2-Y (2000).","journal-title":"Dev Dyn"},{"key":"BFsrep16917_CR49","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1242\/dev.00935","volume":"131","author":"BJ Merrill","year":"2004","unstructured":"Merrill, B. J. et al. Tcf3: a transcriptional regulator of axis induction in the early embryo. Development 131, 263\u2013274, doi: 10.1242\/dev.00935 (2004).","journal-title":"Development"},{"key":"BFsrep16917_CR50","doi-asserted-by":"publisher","first-page":"8692","DOI":"10.1073\/pnas.1100328108","volume":"108","author":"L Qian","year":"2011","unstructured":"Qian, L., Mahaffey, J. P., Alcorn, H. L. & Anderson, K. V. Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo. Proc Natl Acad Sci USA 108, 8692\u20138697, doi: 10.1073\/pnas.1100328108 (2011).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep16917_CR51","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.1242\/dev.02473","volume":"133","author":"AS Rakeman","year":"2006","unstructured":"Rakeman, A. S. & Anderson, K. V. Axis specification and morphogenesis in the mouse embryo require Nap1, a regulator of WAVE-mediated actin branching. Development 133, 3075\u20133083, doi: 10.1242\/dev.02473 (2006).","journal-title":"Development"},{"key":"BFsrep16917_CR52","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.cell.2006.03.048","volume":"125","author":"IE Zohn","year":"2006","unstructured":"Zohn, I. E. et al. p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation. Cell 125, 957\u2013969, doi: 10.1016\/j.cell.2006.03.048 (2006).","journal-title":"Cell"},{"key":"BFsrep16917_CR53","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/S0092-8674(03)00715-3","volume":"114","author":"MJ Garcia-Garcia","year":"2003","unstructured":"Garcia-Garcia, M. J. & Anderson, K. V. Essential role of glycosaminoglycans in Fgf signaling during mouse gastrulation. Cell 114, 727\u2013737 (2003).","journal-title":"Cell"},{"key":"BFsrep16917_CR54","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1002\/bdra.23283","volume":"100","author":"NJ Herion","year":"2014","unstructured":"Herion, N. J., Salbaum, J. M. & Kappen, C. Traffic jam in the primitive streak: The role of defective mesoderm migration in birth defects. Birth Defects Res A Clin Mol Teratol 100, 608\u2013622, doi: 10.1002\/bdra.23283 (2014).","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"BFsrep16917_CR55","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1111\/j.1741-4520.1991.tb00355.x","volume":"31","author":"S Ando","year":"1991","unstructured":"Ando, S., Otani, H., Tanaka, O. & Moritake, K. Morphological Analysis of Neural Tube Defects in Non-obese Diabetic (NOD) Mouse Embryos. Cong. Anom. 31, 23\u201332 (1991).","journal-title":"Cong. Anom."},{"key":"BFsrep16917_CR56","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1038\/nrg1181","volume":"4","author":"AJ Copp","year":"2003","unstructured":"Copp, A. J., Greene, N. D. & Murdoch, J. N. The genetic basis of mammalian neurulation. Nat Rev Genet 4, 784\u2013793, doi: 10.1038\/nrg1181 (2003).","journal-title":"Nat Rev Genet"},{"key":"BFsrep16917_CR57","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/BF00196316","volume":"194","author":"AS Shum","year":"1996","unstructured":"Shum, A. S. & Copp, A. J. Regional differences in morphogenesis of the neuroepithelium suggest multiple mechanisms of spinal neurulation in the mouse. Anat Embryol (Berl) 194, 65\u201373 (1996).","journal-title":"Anat Embryol (Berl)"},{"key":"BFsrep16917_CR58","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1507\/endocrj.K08E-180","volume":"56","author":"K Oyama","year":"2009","unstructured":"Oyama, K. et al. Folic acid prevents congenital malformations in the offspring of diabetic mice. Endocr J 56, 29\u201337 (2009).","journal-title":"Endocr J"},{"key":"BFsrep16917_CR59","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1542\/peds.71.5.815","volume":"71","author":"MJ Khoury","year":"1983","unstructured":"Khoury, M. J., Cordero, J. F., Greenberg, F., James, L. M. & Erickson, J. D. A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics 71, 815\u2013820 (1983).","journal-title":"Pediatrics"},{"key":"BFsrep16917_CR60","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/(SICI)1096-8628(19980401)76:4<291::AID-AJMG3>3.0.CO;2-T","volume":"76","author":"ML Martinez-Frias","year":"1998","unstructured":"Martinez-Frias, M. L., Frias, J. L. & Opitz, J. M. Errors of morphogenesis and developmental field theory. Am J Med Genet 76, 291\u2013296 (1998).","journal-title":"Am J Med Genet"},{"key":"BFsrep16917_CR61","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1006\/dbio.1993.1276","volume":"159","author":"V Garcia-Martinez","year":"1993","unstructured":"Garcia-Martinez, V. & Schoenwolf, G. C. Primitive-streak origin of the cardiovascular system in avian embryos. Dev Biol 159, 706\u2013719, doi: 10.1006\/dbio.1993.1276 (1993).","journal-title":"Dev Biol"},{"key":"BFsrep16917_CR62","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/dvdy.10068","volume":"223","author":"KE Yutzey","year":"2002","unstructured":"Yutzey, K. E. & Kirby, M. L. Wherefore heart thou? Embryonic origins of cardiogenic mesoderm. Dev Dyn 223, 307\u2013320, doi: 10.1002\/dvdy.10068 (2002).","journal-title":"Dev Dyn"},{"key":"BFsrep16917_CR63","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1002\/(SICI)1096-8628(19991119)87:2<99::AID-AJMG1>3.0.CO;2-Q","volume":"87","author":"A Bohring","year":"1999","unstructured":"Bohring, A. et al. Polytopic anomalies with agenesis of the lower vertebral column. Am J Med Genet 87, 99\u2013114 (1999).","journal-title":"Am J Med Genet"},{"key":"BFsrep16917_CR64","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1002\/ajmg.a.32081","volume":"146A","author":"AL Rougemont","year":"2008","unstructured":"Rougemont, A. L. et al. Caudal dysgenesis, sirenomelia and situs inversus totalis: a primitive defect in blastogenesis. Am J Med Genet A 146A, 1470\u20131476, doi: 10.1002\/ajmg.a.32081 (2008).","journal-title":"Am J Med Genet A"},{"key":"BFsrep16917_CR65","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1750-1172-6-56","volume":"6","author":"BD Solomon","year":"2011","unstructured":"Solomon, B. D. VACTERL\/VATER Association. Orphanet J Rare Dis 6, 56, doi: 10.1186\/1750-1172-6-56 (2011).","journal-title":"Orphanet J Rare Dis"},{"key":"BFsrep16917_CR66","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1542\/peds.67.2.176","volume":"67","author":"LJ Russell","year":"1981","unstructured":"Russell, L. J., Weaver, D. D. & Bull, M. J. The axial mesodermal dysplasia spectrum. Pediatrics 67, 176\u2013182 (1981).","journal-title":"Pediatrics"},{"key":"BFsrep16917_CR67","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1002\/tera.1051","volume":"64","author":"CA Loffredo","year":"2001","unstructured":"Loffredo, C. A., Wilson, P. D. & Ferencz, C. Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 64, 98\u2013106, doi: 10.1002\/tera.1051 (2001).","journal-title":"Teratology"},{"key":"BFsrep16917_CR68","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1159\/000346192","volume":"4","author":"RE Stevenson","year":"2013","unstructured":"Stevenson, R. E. & Hunter, A. G. Considering the Embryopathogenesis of VACTERL Association. Mol Syndromol 4, 7\u201315, doi: 10.1159\/000346192 (2013).","journal-title":"Mol Syndromol"},{"key":"BFsrep16917_CR69","first-page":"303","volume":"6","author":"M Depraetere","year":"1995","unstructured":"Depraetere, M., Dehauwere, R., Marien, P. & Fryns, J. P. Severe axial mesodermal dysplasia spectrum in an infant of a diabetic mother. Genet Couns 6, 303\u2013307 (1995).","journal-title":"Genet Couns"},{"key":"BFsrep16917_CR70","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1002\/ajmg.a.31895","volume":"143A","author":"EC Dinleyici","year":"2007","unstructured":"Dinleyici, E. C. et al. Severe fatal course of axial mesodermal dysplasia spectrum associated with complex cardiac defect in an infant of a mother with insulin dependent diabetes. Am J Med Genet A 143A, 2156\u20132159, doi: 10.1002\/ajmg.a.31895 (2007).","journal-title":"Am J Med Genet A"}],"updated-by":[{"DOI":"10.1038\/s41598-022-09478-1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep16917","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16917.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16917.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T18:48:08Z","timestamp":1672944488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep16917"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,23]]},"references-count":70,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,22]]}},"alternative-id":["BFsrep16917"],"URL":"https:\/\/doi.org\/10.1038\/srep16917","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41598-022-09478-1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,23]]},"assertion":[{"value":"13 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2022","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-022-09478-1","URL":"https:\/\/doi.org\/10.1038\/s41598-022-09478-1","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16917"}}