Apoptosis

, Volume 14, Issue 12, pp 1472–1483

Diabetes and apoptosis: neural crest cells and neural tube

  • James H. ChappellJr.
  • Xiao Dan Wang
  • Mary R. Loeken
Diabetes and Apoptosis

Abstract

Birth defects resulting from diabetic pregnancy are associated with apoptosis of a critical mass of progenitor cells early during the formation of the affected organ(s). Insufficient expression of genes that regulate viability of the progenitor cells is responsible for the apoptosis. In particular, maternal diabetes inhibits expression of a gene, Pax3, that encodes a transcription factor which is expressed in neural crest and neuroepithelial cells. As a result of insufficient Pax3, cardiac neural crest and neuroepithelial cells undergo apoptosis by a process dependent on the p53 tumor suppressor protein. This, then provides a cellular explanation for the cardiac outflow tract and neural tube and defects induced by diabetic pregnancy.

Keywords

Diabetic pregnancy Congenital defects Neural tube defect Cardiac outflow tract defect Apoptosis Oxidative stress Pax3 p53 

Abbreviations

T1DM

Type 1 diabetes mellitus

T2DM

Type 2 diabetes mellitus

STZ

Streptozotocin

NTD

Neural tube defect(s)

COTD

Cardiac outflow tract defect(s)

CNC

Cardiac neural crest

Glut

Glucose transporter(s)

GSH

Reduced glutathione

GSSG

Oxidized glutathione

References

  1. 1.
    Farrell T, Neale L, Cundy T (2002) Congenital anomalies in the offspring of women with type 1, type 2 and gestational diabetes. Diabet Med 19:322–326PubMedCrossRefGoogle Scholar
  2. 2.
    White P (1949) Pregnancy complicating diabetes. Am J Med 7:609–616PubMedCrossRefGoogle Scholar
  3. 3.
    Correa A, Gilboa SM, Besser LM et al (2008) Diabetes mellitus and birth defects. Am J Obstet Gynecol 199:237.e1–237.e9CrossRefGoogle Scholar
  4. 4.
    Mills JL, Knopp RH, Simpson JL et al (1988) Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. N Eng J Med 318:671–676CrossRefGoogle Scholar
  5. 5.
    Miodovnik M, Mimouni F, Dignan PSJ et al (1988) Major malformations in infants of IDDM women: vasculopathy and early first-trimester poor glycemic control. Diabetes Care 11:713–718PubMedCrossRefGoogle Scholar
  6. 6.
    Loffredo CA, Wilson PD, Ferencz C (2001) Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology 64:98–106PubMedCrossRefGoogle Scholar
  7. 7.
    Kitzmiller JL, Cloherty JP, Younger MD et al (1978) Diabetic pregnancy and perinatal morbidity. Am J Obstet Gynecol 131:560–580PubMedGoogle Scholar
  8. 8.
    Hawthorne G, Robson S, Ryall EA, Sen D, Roberts SH, Ward Platt MP (1997) Prospective population based survey of outcome of pregnancy in diabetic women: results of the Northern Diabetic Pregnancy Audit, 1994. Br Med J 315:279–281Google Scholar
  9. 9.
    Greene MF, Hare JW, Cloherty JP, Benacerraf BR, Soeldner JS (1989) First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 39:225–231PubMedCrossRefGoogle Scholar
  10. 10.
    The DCCT Research Group (1996) Pregnancy outcomes in the diabetes control and complications trial. Am J Obstet Gynecol 174:1343–1353CrossRefGoogle Scholar
  11. 11.
    Langer O, Conway DL (2000) Level of glycemia and perinatal outcome in pregestational diabetes. J Matern Fetal Med 9:35–41PubMedCrossRefGoogle Scholar
  12. 12.
    Suhonen L, Hiilesmaa V, Teramo K (2000) Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 43:79–82PubMedCrossRefGoogle Scholar
  13. 13.
    Aberg A, Westbom L, Kallen B (2001) Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev 61:85–95PubMedCrossRefGoogle Scholar
  14. 14.
    Freinkel N (1980) Of pregnancy and progeny. Diabetes 29:1023–1035PubMedCrossRefGoogle Scholar
  15. 15.
    Moore LL, Singer MR, Bradlee ML, Rothman KJ, Milunsky A (2000) A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology 11:689–694PubMedCrossRefGoogle Scholar
  16. 16.
    Shaw GM, Velie EM, Schaffer D (1996) Risk of neural tube defect-affected pregnancies among obese women. JAMA 275:1093–1096PubMedCrossRefGoogle Scholar
  17. 17.
    Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA (2003) Maternal obesity and risk for birth defects. Pediatrics 111:1152–1158PubMedGoogle Scholar
  18. 18.
    Werler MW, Louik C, Shapiro S, Mitchell AA (1996) Prepregnant weight in relation to risk of neural tube defects. JAMA 275:1089–1092PubMedCrossRefGoogle Scholar
  19. 19.
    Waller DK, Shaw GM, Rasmussen SA et al (2007) Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatr Adolesc Med 161:745–750PubMedCrossRefGoogle Scholar
  20. 20.
    MRC Vitamin Research Group (1991) Prevention of neural tube defects: results of the MRC vitamin study. Lancet 338:132–137Google Scholar
  21. 21.
    Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LYC (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285:2981–2986PubMedCrossRefGoogle Scholar
  22. 22.
    De Wals P, Tairou F, Van Allen MI et al (2007) Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 357:135–142PubMedCrossRefGoogle Scholar
  23. 23.
    Laraia BA, Bodnar LM, Siega-Riz AM (2007) Pregravid body mass index is negatively associated with diet quality during pregnancy. Public Health Nutr 10:920–926PubMedCrossRefGoogle Scholar
  24. 24.
    Case AP, Ramadhani TA, Canfield MA, Beverly L, Wood R (2007) Folic acid supplementation among diabetic, overweight, or obese women of childbearing age. J Obstet Gynecol Neonatal Nurs 36:335–341PubMedCrossRefGoogle Scholar
  25. 25.
    Mahabir S, Ettinger S, Johnson L et al (2008) Measures of adiposity and body fat distribution in relation to serum folate levels in postmenopausal women in a feeding study. Eur J Clin Nutr 62:644–650PubMedCrossRefGoogle Scholar
  26. 26.
    Becerra JE, Khoury MJ, Cordero JF, Erickson JD (1990) Diabetes mellitus during pregnancy and the risks for the specific birth defects: a population-based case-control study. Pediatrics 85:1–9PubMedGoogle Scholar
  27. 27.
    Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL (2000) Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol 182:313–320PubMedCrossRefGoogle Scholar
  28. 28.
    Nielsen GL, Norgard B, Puho E, Rothman KJ, Sorensen HT, Czeizel AE (2005) Risk of specific congenital abnormalities in offspring of women with diabetes. Diabet Med 22:693–696PubMedCrossRefGoogle Scholar
  29. 29.
    Macintosh MCM, Fleming KM, Bailey JA et al (2006) Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. Br Med J 333:177–180CrossRefGoogle Scholar
  30. 30.
    Mills JL, Baker L, Goldman AS (1979) Malformations in infants of diabetic mothers occur before the seventh gestational week: implications for treatment. Diabetes 28:292–293PubMedCrossRefGoogle Scholar
  31. 31.
    Hod M, Star S, Passonneau JV, Unterman TG, Freinkel N (1986) Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: failure of aldose reductase inhibitors to modify myo-inositol depletion and dysmorphogenesis. Biochem Biophys Res Commun 140:974–980PubMedCrossRefGoogle Scholar
  32. 32.
    Buchanan TA, Denno KM, Sipos GF, Sadler TW (1994) Diabetic teratogenesis: in vitro evidence for a multifactorial etiology with little contribution from glucose per se. Diabetes 43:656–660PubMedCrossRefGoogle Scholar
  33. 33.
    Eriksson UJ, Hakan Borg LA, Forsberg H, Styrud J (1991) Diabetic embryopathy: studies with animal and in vitro models. Diabetes 40(Suppl. 2):94–98PubMedGoogle Scholar
  34. 34.
    Sadler TW, Hunter ESI, Wynn RE, Phillips LS (1989) Evidence for multifactorial origin of diabetes-induced embryopathies. Diabetes 38:70–74PubMedCrossRefGoogle Scholar
  35. 35.
    Reece EA, Pinter E, Leranth CZ et al (1985) Ultrastructural analysis of malformations of the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology 32:363–373PubMedCrossRefGoogle Scholar
  36. 36.
    Zusman I, Yaffe P, Ornoy A (1987) Effects of metabolic factors in the diabetic state on the in vitro development of preimplantation mouse embryos. Teratology 35:77–85PubMedCrossRefGoogle Scholar
  37. 37.
    Viana M, Herrera E, Bonet B (1996) Terotogenic effects of diabetes mellitus in the rat. Prevention by vitamin E. Diabetologia 39:1041–1046PubMedCrossRefGoogle Scholar
  38. 38.
    Gareskog M, Wentzel P (2004) Altered protein kinase C activation associated with rat embryonic dysmorphogenesis. Pediatr Res 56:849–857PubMedCrossRefGoogle Scholar
  39. 39.
    Gareskog M, Wentzel P (2007) N-Acetylcysteine and alpha-cyano-4-hydroxycinnamic acid alter protein kinase C (PKC)-delta and PKC-zeta and diminish dysmorphogenesis in rat embryos cultured with high glucose in vitro. J Endocrinol 192:207–214PubMedCrossRefGoogle Scholar
  40. 40.
    Hiramatsu Y, Sekiguchi N, Hayashi M et al (2002) Diacylglycerol production and protein kinase C activity are increased in a mouse model of diabetic embryopathy. Diabetes 51:2804–2810PubMedCrossRefGoogle Scholar
  41. 41.
    Engstrom E, Haglund A, Eriksson UJ (1991) Effects of maternal diabetes or in vitro hyperglycemia on uptake of palmitic and arachidonic acid by rat embryos. Pediatr Res 30:150–153PubMedGoogle Scholar
  42. 42.
    Goldman AS, Baker L, Piddington R, Marx B, Herold R, Egler J (1985) Hyperglycemic-induced teratogenesis is mediated by a functional deficiency of arachidonic acid. Proc Natl Acad Sci USA 82:8227–8231PubMedCrossRefGoogle Scholar
  43. 43.
    Schoenfeld A, Erman A, Warchaizer S, Ovadia J, Bonner J, Hod M (1995) Yolk sac concentration of prostaglandin E(2) in diabetic pregnancy: further clues to the etiology of diabetic embryopathy. Prostaglandins 50:121–126PubMedCrossRefGoogle Scholar
  44. 44.
    Wentzel P, Welsh N, Eriksson UJ (1999) Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered prostaglandin E2 levels in rat embryos exposed to a diabetic environment. Diabetes 48:813–820PubMedCrossRefGoogle Scholar
  45. 45.
    Higa R, Gonzalez E, Pustovrh MC et al (2007) PPARdelta and its activator PGI2 are reduced in diabetic embryopathy: involvement of PPARdelta activation in lipid metabolic and signalling pathways in rat embryo early organogenesis. Mol Hum Reprod 13:103–110PubMedCrossRefGoogle Scholar
  46. 46.
    Capobianco E, Martinez N, Higa R, White V, Jawerbaum A (2008) The effects of maternal dietary treatments with natural PPAR ligands on lipid metabolism in fetuses from control and diabetic rats. Prostaglandins Leukot Essent Fatty Acids 79:191–199PubMedCrossRefGoogle Scholar
  47. 47.
    Capobianco E, White V, Higa R, Martinez N, Jawerbaum A (2008) Effects of natural ligands of PPARgamma on lipid metabolism in placental tissues from healthy and diabetic rats. Mol Hum Reprod 14:491–499PubMedCrossRefGoogle Scholar
  48. 48.
    Martinez N, Capobianco E, White V, Pustovrh MC, Higa R, Jawerbaum A (2008) Peroxisome proliferator-activated receptor alpha activation regulates lipid metabolism in the feto-placental unit from diabetic rats. Reproduction 136:95–103PubMedCrossRefGoogle Scholar
  49. 49.
    Lee AT, Plump A, DeSimone C, Cerami A, Bucala R (1995) A role for DNA mutations in diabetes-associated teratogensis in transgeneic embryos. Diabetes 44:20–24PubMedCrossRefGoogle Scholar
  50. 50.
    Lee AT, Reis D, Eriksson UJ (1999) Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo. Diabetes 48:371–376PubMedCrossRefGoogle Scholar
  51. 51.
    Siman CM, Eriksson UJ (1997) Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes 46:1054–1061PubMedCrossRefGoogle Scholar
  52. 52.
    Sivan E, Reece EA, Wu YK, Homko CJ, Polansky M, Borenstein M (1996) Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol 175:793–799PubMedCrossRefGoogle Scholar
  53. 53.
    Wentzel P, Eriksson UJ (1998) Antioxidants diminish developmental damage induced by high glucose and cyclooxygenase inhibitors in rat embryos in vitro. Diabetes 47:677–684PubMedCrossRefGoogle Scholar
  54. 54.
    Hagay ZJ, Weiss Y, Zusman I et al (1995) Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos. Am J Obstet Gynecol 173:1036–1041PubMedCrossRefGoogle Scholar
  55. 55.
    Weksler-Zangen S, Yaffe P, Ornoy A (2003) Reduced SOD activity and increased neural tube defects in embryos of the sensitive but not of the resistant Cohen diabetic rats cultured under diabetic conditions. Birth Defects Res A Clin Mol Teratol 67:429–437PubMedCrossRefGoogle Scholar
  56. 56.
    Copp AJ (2005) Neurulation in the cranial region—normal and abnormal. J Anat 207:623–635PubMedGoogle Scholar
  57. 57.
    Lawson A, England MA (1998) Neural fold fusion in the cranial region of the chick embryo. Dev Dyn 212:473–481PubMedCrossRefGoogle Scholar
  58. 58.
    Weil M, Jacobson MD, Raff MC (1997) Is programmed cell death required for neural tube closure? Curr Biol 7:281–284PubMedCrossRefGoogle Scholar
  59. 59.
    Naruse I, Keino H (1995) Apoptosis in the developing CNS. Prog Neurobiol 47:135–155PubMedCrossRefGoogle Scholar
  60. 60.
    Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94:727–737PubMedCrossRefGoogle Scholar
  61. 61.
    Mori C, Nakamura N, Okamoto Y, Osawa M, Shiota K (1994) Cytochemical identification of programmed cell death in the fusing fetal mouse palate by specific labelling of DNA fragmentation. Anat Embryol 190:21–28PubMedCrossRefGoogle Scholar
  62. 62.
    Lynch MP, Capparelli C, Stein JL, Stein GS, Lian JB (1998) Apoptosis during bone-like tissue development in vitro. J Cell Biochem 68:31–49PubMedCrossRefGoogle Scholar
  63. 63.
    Homma S, Yaginuma H, Oppenheim RW (1994) Programmed cell death during the earliest stages of spinal cord development in the chick embryo: a possible means of early phenotypic selection. J Comp Neurol 345:377–395PubMedCrossRefGoogle Scholar
  64. 64.
    Graham A, Heyman I, Lumsden A (1993) Even-numbered rhombomeres control the apoptotic elimination of neural crest cells from odd-numbered rhombomeres in the chick hindbrain. Development 119:233–245PubMedGoogle Scholar
  65. 65.
    Clarke PG (1990) Developmental cell death: morphological diversity and multiple mechnisms. Anat Embryol 181:195–213PubMedCrossRefGoogle Scholar
  66. 66.
    Sulik KK, Cook CS, Webster WS (1988) Teratogens and craniofacial malformations: relationships to cell death. Development 103(Suppl.):213–232PubMedGoogle Scholar
  67. 67.
    Walther C, Guenet JL, Simon D et al (1991) Pax: a murine multigene family of paired box-containing genes. Genomics 11:424–434PubMedCrossRefGoogle Scholar
  68. 68.
    Chalepakis G, Tremblay P, Gruss P (1992) Pax genes, mutants and molecular function. J Cell Sci Suppl 16:61–67PubMedGoogle Scholar
  69. 69.
    Gruss P, Walther C (1992) Pax in development. Cell 69:719–722PubMedCrossRefGoogle Scholar
  70. 70.
    Stuart ET, Kioussi C, Gruss P (1994) Mammalian pax genes. Ann Rev Genet 28:219–236PubMedCrossRefGoogle Scholar
  71. 71.
    Robson EJ, He SJ, Eccles MR (2006) A PANorama of PAX genes in cancer and development. Nat Rev Cancer 6:52–62PubMedCrossRefGoogle Scholar
  72. 72.
    Goulding MD, Chalepakis G, Deutsch U, Erselius JR, Gruss P (1991) Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO J 10:1135–1147PubMedGoogle Scholar
  73. 73.
    Chalepakis G, Goulding M, Read A, Strachan T, Gruss P (1994) Molecular basis of splotch and Waardenburg Pax-3 mutations. Proc Natl Acad Sci USA 91:3685–3689PubMedCrossRefGoogle Scholar
  74. 74.
    Lalwani AK, Brister JR, Fex J et al (1995) Further elucidation of the genomic structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome type 1 in two families. Am J Hum Genet 56:75–83PubMedGoogle Scholar
  75. 75.
    Waardenburg PJ (1951) A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet 3:195–253PubMedGoogle Scholar
  76. 76.
    Epstein DJ, Vekemans M, Gros P (1991) Splotch (Sp-2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell 67:767–774PubMedCrossRefGoogle Scholar
  77. 77.
    Epstein DJ, Vogan KJ, Trasler DG, Gros P (1993) A mutation within intron 3 of the Pax-3 gene produces aberrantly spliced mRNA transcripts in the splotch (Sp) mouse mutant. Proc Natl Acad Sci USA 90:532–536PubMedCrossRefGoogle Scholar
  78. 78.
    Goulding M, Sterrer S, Fleming J et al (1993) Analysis of the Pax-3 gene in the mouse mutant splotch. Genomics 17:355–363PubMedCrossRefGoogle Scholar
  79. 79.
    Vogan KJ, Epstein DJ, Trasler DG, Gros P (1993) The Splotch-delayed (Sp-d) mouse mutant carries a point mutation within the paired box of the Pax-3 gene. Genomics 17:364–369PubMedCrossRefGoogle Scholar
  80. 80.
    Auerbach R (1954) Analysis of the developmental effects of a lethal mutation in the house mouse. J Exp Zool 127:305–329CrossRefGoogle Scholar
  81. 81.
    Franz T (1989) Persistent truncus arteriosus in the Splotch mutant mouse. Anat Embryol (Berl) 180:457–464CrossRefGoogle Scholar
  82. 82.
    St Amand TR, Lu JT, Zamora M et al (2006) Distinct roles of HF-1b/Sp4 in ventricular and neural crest cells lineages affect cardiac conduction system development. Dev Biol 291:208–217PubMedCrossRefGoogle Scholar
  83. 83.
    Epstein JA, Li J, Lang D et al (2000) Migration of cardiac neural crest cells in Splotch embryos. Development 127:1869–1878PubMedGoogle Scholar
  84. 84.
    Conway SJ, Godt RE, Hatcher CJ et al (1997) Neural crest is involved in development of abnormal myocardial function. J Mol Cell Cardiol 29:2675–2685PubMedCrossRefGoogle Scholar
  85. 85.
    Conway SJ, Henderson DJ, Kirby ML, Anderson RH, Copp AJ (1997) Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. Cardiovasc Res 36:163–173PubMedCrossRefGoogle Scholar
  86. 86.
    Phelan SA, Ito M, Loeken MR (1997) Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes 46:1189–1197PubMedCrossRefGoogle Scholar
  87. 87.
    Morgan SC, Relaix F, Sandell LL, Loeken MR (2008) Oxidative stress during diabetic pregnancy disrupts cardiac neural crest migration and causes outflow tract defects. Birth Defects Res A Clin Mol Teratol 82:453–463PubMedCrossRefGoogle Scholar
  88. 88.
    Maulbecker CC, Gruss P (1993) The oncogenic potential of Pax genes. EMBO J 12:2361–2367PubMedGoogle Scholar
  89. 89.
    Barr FG, Fitzgerald JC, Ginsberg JP, Vanella ML, Davis RJ, Bennicelli JL (1999) Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines. Cancer Res 59:5443–5448PubMedGoogle Scholar
  90. 90.
    Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS (1993) Rearrangement of the PAX3 paired box gene in the paediatric solid tumor alveolar rhabdomyosarcoma. Nature Genet 3:113–117PubMedCrossRefGoogle Scholar
  91. 91.
    Galili N, Davis R, Fredericks WJ et al (1993) Fusion of a fork head domain gene to PAX3 in the solid tumor alveolar rhabdomyosarcoma. Nature Genet 5:230–235PubMedCrossRefGoogle Scholar
  92. 92.
    Shapiro DN, Sublett JE, Li B, Downing JR, Naeve CW (1993) Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 53:5108–5112PubMedGoogle Scholar
  93. 93.
    Blake J, Ziman MR (2003) Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma? Histol Histopathol 18:529–539PubMedGoogle Scholar
  94. 94.
    Gershon TR, Oppenheimer O, Chin SS, Gerald WL (2005) Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia 7:575–584PubMedCrossRefGoogle Scholar
  95. 95.
    Schulte TW, Toretsky JA, Ress E, Helman L, Neckers LM (1997) Expression of PAX3 in Ewing’s sarcoma family of tumors. Biochem Mol Med 60:121–126PubMedCrossRefGoogle Scholar
  96. 96.
    Kubic JD, Young KP, Plummer RS, Ludvik AE, Lang D (2008) Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease. Pigment Cell Melanoma Res 21:627–645PubMedCrossRefGoogle Scholar
  97. 97.
    Vachtenheim J, Novotna H (1999) Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human melanomas. Cell Mol Biol (Noisy-le-grand) 45:1075–1082Google Scholar
  98. 98.
    Scholl FA, Kamarashev J, Murmann OV, Geertsen R, Dummer R, Schafer BW (2001) PAX3 is expressed in human melanomas and contributes to tumor cell survival. Cancer Res 61:823–826PubMedGoogle Scholar
  99. 99.
    He SJ, Stevens G, Braithwaite AW, Eccles MR (2005) Transfection of melanoma cells with antisense PAX3 oligonucleotides additively complements cisplatin-induced cytotoxicity. Mol Cancer Ther 4:996–1003PubMedCrossRefGoogle Scholar
  100. 100.
    Bernasconi M, Remppis A, Fredericks WJ, Rauscher FJ, Schafer BW (1996) Induction of apoptosis in rhabdomyosarcoma cells through down-regulation of PAX proteins. Proc Natl Acad Sci USA 93:13164–13169PubMedCrossRefGoogle Scholar
  101. 101.
    Yang G, Li Y, Nishimura EK et al (2008) Inhibition of PAX3 by TGF-beta modulates melanocyte viability. Mol Cell 32:554–563PubMedCrossRefGoogle Scholar
  102. 102.
    Morgan SC, Lee H-Y, Relaix F, Sandell L, Lavorse J, Loeken MR (2008) Cardiac outflow tract septation failure in Pax3-deficient embryos is due to p53-dependent regulation of migrating cardiac neural crest. Mech Dev 125:757–767PubMedCrossRefGoogle Scholar
  103. 103.
    Sadler TW (2005) Embryology of neural tube development. Am J Med Genet C Semin Med Genet 135C:2–8PubMedCrossRefGoogle Scholar
  104. 104.
    Salvarezza SB, Rovasio RA (1997) Exogenous retinoic acid decreases in vivo and in vitro proliferative activity during the early migratory stage of neural crest cells. Cell Prolif 30:71–80PubMedCrossRefGoogle Scholar
  105. 105.
    Sun FY, Kawasaki E, Akazawa S et al (2005) Apoptosis and its pathway in early post-implantation embryos of diabetic rats. Diabetes Res Clin Pract 67:110–118PubMedCrossRefGoogle Scholar
  106. 106.
    Jiang B, Kumar SD, Loh WT et al (2008) Global gene expression analysis of cranial neural tubes in embryos of diabetic mice. J Neurosci Res 86:3481–3493PubMedCrossRefGoogle Scholar
  107. 107.
    Gao Q, Gao YM (2007) Hyperglycemic condition disturbs the proliferation and cell death of neural progenitors in mouse embryonic spinal cord. Int J Dev Neurosci 25:349–357PubMedCrossRefGoogle Scholar
  108. 108.
    Wentzel P, Gareskog M, Eriksson UJ (2008) Decreased cardiac glutathione peroxidase levels and enhanced mandibular apoptosis in malformed embryos of diabetic rats. Diabetes 57:3344–3352PubMedCrossRefGoogle Scholar
  109. 109.
    Kumar SD, Dheen ST, Tay SS (2007) Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol 6:34PubMedCrossRefGoogle Scholar
  110. 110.
    Molin DG, Roest PA, Nordstrand H et al (2004) Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats. Birth Defects Res A Clin Mol Teratol 70:927–938PubMedCrossRefGoogle Scholar
  111. 111.
    Gareskog M, Cederberg J, Eriksson UJ, Wentzel P (2007) Maternal diabetes in vivo and high glucose concentration in vitro increases apoptosis in rat embryos. Reprod Toxicol 23:63–74PubMedCrossRefGoogle Scholar
  112. 112.
    Loeken MR (2006) Advances in understanding the molecular causes of diabetes-induced birth defects. J Soc Gynecol Investig 13:2–10PubMedCrossRefGoogle Scholar
  113. 113.
    Horton WE Jr, Sadler TW (1983) Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate. Diabetes 32:610–616PubMedCrossRefGoogle Scholar
  114. 114.
    Unterman TG, Buchanan TA, Freinkel N (1989) Access of maternal insulin to the rat conceptus prior to allantoic placentation. Diabetes Res 10:115–120PubMedGoogle Scholar
  115. 115.
    Towner D, Kjos SL, Leung B et al (1995) Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 18:1446–1451PubMedCrossRefGoogle Scholar
  116. 116.
    Schaefer UM, Sonster G, Xiang A, Berkowitz K, Buchanan TA, Kjos SL (1997) Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy. Am J Obstet Gynecol 177:1165–1171PubMedCrossRefGoogle Scholar
  117. 117.
    Lauenborg J, Mathiesen E, Ovesen P et al (2003) Audit on stillbirths in women with pregestational type 1 diabetes. Diabetes Care 26:1385–1389PubMedCrossRefGoogle Scholar
  118. 118.
    Sussman I, Matschinsky FM (1988) Diabetes affects sorbitol and myo-inositol levels of neuroectodermal tissue during embryogenesis in rat. Diabetes 37:974–981PubMedCrossRefGoogle Scholar
  119. 119.
    Fine E, Horal M, Chang T, Fortin G, Loeken M (1999) Evidence that hyperglycemia causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes 48:2454–2462PubMedCrossRefGoogle Scholar
  120. 120.
    Hogan A, Heyner S, Charon MJ et al (1991) Glucose transporter gene expression in early mouse embryos. Development 113:363–372PubMedGoogle Scholar
  121. 121.
    Li R, Thorens B, Loeken MR (2007) Expression of the gene encoding the high Km glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy. Diabetologia 50:682–689PubMedCrossRefGoogle Scholar
  122. 122.
    Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMedCrossRefGoogle Scholar
  123. 123.
    Sakamaki H, Akazawa S, Ishibashi M et al (1999) Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations. Diabetes 48:1138–1144PubMedCrossRefGoogle Scholar
  124. 124.
    Trocino RA, Akazawa S, Ishibashi M et al (1995) Significance of glutathione depletion and oxidative stress in early embryogenesis in glucose-induced rat embryo culture. Diabetes 44:992–998PubMedCrossRefGoogle Scholar
  125. 125.
    Horal M, Zhang Z, Virkamaki A, Stanton R, Loeken MR (2004) Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: involvement in diabetic teratogenesis. Birth Defects Res Part A Clin Mol Teratol 70:519–527PubMedCrossRefGoogle Scholar
  126. 126.
    Li R, Chase M, Jung SK, Smith PJS, Loeken MR (2005) Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. Am J Physiol Endocrinol Metab 289:E591–E599PubMedCrossRefGoogle Scholar
  127. 127.
    Jabs T (1999) Reactive oxygen intermediates as mediators of programmed cell death in plants and animals. Biochem Pharmacol 57:231–245PubMedCrossRefGoogle Scholar
  128. 128.
    Chang TI, Horal M, Jain S, Wang F, Patel R, Loeken MR (2003) Oxidant regulation of gene expression and neural tube development: insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 46:538–545PubMedCrossRefGoogle Scholar
  129. 129.
    Agrawal A, Choudhary D, Upreti M, Rath PC, Kale RK (2001) Radiation induced oxidative stress: I. Studies in Ehrlich solid tumor in mice. Mol Cell Biochem 223:71–80PubMedCrossRefGoogle Scholar
  130. 130.
    Nicol CJ, Zielenski J, Tsui LC, Wells PG (2000) An embryoprotective role for glucose-6-phosphate dehydrogenase in developmental oxidative stress and chemical teratogenesis. FASEB J 14:111–127PubMedGoogle Scholar
  131. 131.
    Nakano E, Higgins JA, Powers HJ (2001) Folate protects against oxidative modification of human LDL. Br J Nutr 86:637–639PubMedCrossRefGoogle Scholar
  132. 132.
    Chern CL, Huang RF, Chen YH, Cheng JT, Liu TZ (2001) Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-kappaB in human Hep G2 cells. Biomed Pharmacother 55:434–442PubMedCrossRefGoogle Scholar
  133. 133.
    Rosenquist TH, Ratashak SA, Selhub J (1996) Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA 93:15227–15232PubMedCrossRefGoogle Scholar
  134. 134.
    Zabihi S, Eriksson UJ, Wentzel P (2007) Folic acid supplementation affects ROS scavenging enzymes, enhances Vegf-A, and diminishes apoptotic state in yolk sacs of embryos of diabetic rats. Reprod Toxicol 23:486–498PubMedCrossRefGoogle Scholar
  135. 135.
    Oyama K, Sugimura Y, Murase T et al (2008) Folic acid prevents congenital malformations in the offspring of diabetic mice. Endocr J 56:29–37 PubMedCrossRefGoogle Scholar
  136. 136.
    Fleming A, Copp AJ (1998) Embryonic folate metabolism and mouse neural tube defects. Science 280:2107–2109PubMedCrossRefGoogle Scholar
  137. 137.
    Gefrides LA, Bennett GD, Finnell RH (2002) Effects of folate supplementation on the risk of spontaneous and induced neural tube defects in Splotch mice. Teratology 65:63–69PubMedCrossRefGoogle Scholar
  138. 138.
    Kaplan JS, Iqbal S, England BG, Zawacki CM, Herman WH (1999) Is pregnancy in diabetic women associated with folate deficiency? Diabetes Care 22:1017–1021PubMedCrossRefGoogle Scholar
  139. 139.
    Pani L, Horal M, Loeken MR (2002) Polymorphic susceptibility to the molecular causes of neural tube defects during diabetic embryopathy. Diabetes 51:2871–2874PubMedCrossRefGoogle Scholar
  140. 140.
    Jacks T, Remington L, William BO et al (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4:1–7PubMedCrossRefGoogle Scholar
  141. 141.
    Komarov PG, Komarova EA, Kondratov RV et al (1999) A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285:1733–1737PubMedCrossRefGoogle Scholar
  142. 142.
    Endo H, Saito A, Chan PH (2006) Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia. Biochem Soc Trans 34:1283–1286PubMedCrossRefGoogle Scholar
  143. 143.
    Murphy PJ, Galigniana MD, Morishima Y et al (2004) Pifithrin-alpha inhibits p53 signaling after interaction of the tumor suppressor protein with hsp90 and its nuclear translocation. J Biol Chem 279:30195–30201PubMedCrossRefGoogle Scholar
  144. 144.
    Chan WY, Cheung CS, Yung KM, Copp AJ (2004) Cardiac neural crest of the mouse embryo: axial level of origin, migratory pathway and cell autonomy of the splotch (Sp2H) mutant effect. Development 131:3367–3379PubMedCrossRefGoogle Scholar
  145. 145.
    Kirby ML, Gale TF, Stewart DE (1983) Neural crest cells contribute to normal aorticopulmonary septation. Science 220:1059–1061PubMedCrossRefGoogle Scholar
  146. 146.
    Besson WT, Kirby ML, Mierop LHV, Teabeaut JR (1986) Effects of the size of lesions of the cardiac neural crest at various embryonic ages on incidence and type of cardiac defects. Circulation 73:360–364PubMedGoogle Scholar
  147. 147.
    Nishibatake M, Kirby ML, Mierop LHV (1987) Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. Circulation 75:255–264PubMedGoogle Scholar
  148. 148.
    Bockman DE, Redmond ME, Waldo K, Davis H, Kirby ML (1987) Effect of neural crest ablation on development of the heart and arch arteries in the chick. Am J Anat 180:332–341PubMedCrossRefGoogle Scholar
  149. 149.
    Moase CE, Trasler DG (1990) Delayed neural crest cell emigration from Sp and Spd mouse neural tube explants. Teratology 42:171–182PubMedCrossRefGoogle Scholar
  150. 150.
    Pani L, Horal M, Loeken MR (2002) Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3- dependent development and tumorigenesis. Genes Dev 16:676–680PubMedCrossRefGoogle Scholar
  151. 151.
    Stuart ET, Haffner R, Oren M, Gruss P (1995) Loss of p53 function through PAX-mediated transcriptional repression. EMBO J 14:5638–5645PubMedGoogle Scholar
  152. 152.
    Fu L, Ma W, Benchimol S (1999) A translation repressor element resides in the 3′ untranslated region of human p53 mRNA. Oncogene 18:6419–6424PubMedCrossRefGoogle Scholar
  153. 153.
    Mazan-Mamczarz K, Galban S, Lopez De Silanes I et al (2003) RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc Natl Acad Sci USA 100:8354–8359PubMedCrossRefGoogle Scholar
  154. 154.
    Appella E, Anderson CW (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268:2764–2772PubMedCrossRefGoogle Scholar
  155. 155.
    Underwood TJ, Amin J, Lillycrop KA, Blaydes JP (2007) Dissection of the functional interaction between p53 and the embryonic proto-oncoprotein PAX3. FEBS Lett 581:5831–5835PubMedCrossRefGoogle Scholar
  156. 156.
    Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270PubMedGoogle Scholar
  157. 157.
    Warburg O (1956) On the origin of cancer cells. Science 123:309–314PubMedCrossRefGoogle Scholar
  158. 158.
    Kondoh H, Lleonart ME, Gil J et al (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65:177–185PubMedGoogle Scholar
  159. 159.
    Ma W, Sung HJ, Park JY, Matoba S, Hwang PM (2007) A pivotal role for p53: balancing aerobic respiration and glycolysis. J Bioenerg Biomembr 39:243–246PubMedCrossRefGoogle Scholar
  160. 160.
    Olivotto M, Caldini R, Chevanne M, Cipolleschi MG (1983) The respiration-linked limiting step of tumor cell transition from the non-cycling to the cycling state: its inhibition by oxidizable substrates and its relationships to purine metabolism. J Cell Physiol 116:149–158PubMedCrossRefGoogle Scholar
  161. 161.
    Doblado M, Moley KH (2007) Glucose metabolism in pregnancy and embryogenesis. Curr Opin Endocrinol Diabetes Obes 14:488–493PubMedGoogle Scholar
  162. 162.
    Jungheim ES, Moley KH (2008) The impact of type 1 and type 2 diabetes mellitus on the oocyte and the preimplantation embryo. Semin Reprod Med 26:186–195PubMedCrossRefGoogle Scholar
  163. 163.
    Diamond MP, Moley KH, Pellicer A, Vaughn WK, DeCherney AH (1989) Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development. J Reprod Fertil 86:1–10PubMedCrossRefGoogle Scholar
  164. 164.
    Beebe LFS, Kaye PL (1991) Maternal diabetes and retarded preimplantation development of mice. Diabetes 40:457–461PubMedCrossRefGoogle Scholar
  165. 165.
    Chang AS, Dale AN, Moley KH (2005) Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis. Endocrinology 146:2445–2453PubMedCrossRefGoogle Scholar
  166. 166.
    Lea RG, McCracken JE, McIntryre SS, Smith W, Baird JD (1996) Disturbed development of the preimplantation embryo in the insulin-dependent diabetic BB/E rat. Diabetes 45:1463–1470PubMedCrossRefGoogle Scholar
  167. 167.
    Diamond MP, Harbert-Moley K, Logan J et al (1990) Manifestation of diabetes mellitus on mouse follicular and pre-embryo development: effect of hyperglycemia per se. Metabolism 39:220–224PubMedCrossRefGoogle Scholar
  168. 168.
    Diamond MP, Pettway ZY, Logan J, Moley K, Vaughn W, DeCherney AH (1991) Dose-response effects of glucose, insulin, and glucagon on mouse pre-embryo development. Metabolism 40:566–570PubMedCrossRefGoogle Scholar
  169. 169.
    Pampfer S, DeHertogh R, Venderheyden I, Michiels B, Vercheval M (1990) Decreased inner cell mass proportion in blastocysts from diabetic rats. Diabetes 39:471–476PubMedCrossRefGoogle Scholar
  170. 170.
    Pampfer S, Vanderheyden I, McCracken JE, Vesela J, DeHertogh R (1997) Increased cell death in rat blastocysts exposed to maternal diabetes in utero and to high glucose or tumor necrosis factor-a in vitro. Development 124:4827–4836PubMedGoogle Scholar
  171. 171.
    Leunda-Casi A, Genicot G, Donnay I, Pampfer S, De Hertogh R (2002) Increased cell death in mouse blastocysts exposed to high d-glucose in vitro: implications of an oxidative stress and alterations in glucose metabolism. Diabetologia 45:571–579PubMedCrossRefGoogle Scholar
  172. 172.
    Moley KH, Chi MM, Knudson CM, Korsmeyer SJ, Mueckler MM (1998) Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways. Nat Med 4:1421–1424PubMedCrossRefGoogle Scholar
  173. 173.
    Keim AL, Chi MM, Moley KH (2001) Hyperglycemia-induced apoptotic cell death in the mouse blastocyst is dependent on expression of p53. Mol Reprod Dev 60:214–224PubMedCrossRefGoogle Scholar
  174. 174.
    Moley KH, Chi MMY, Mueckler MM (1998) Maternal hyperglycemia alters glucose transport and utilization in mouse preimplantation embryos. Am J Phys Endocrinol Metab 38:E38–E47Google Scholar
  175. 175.
    Carayannopoulos MO, Chi MM, Cui Y et al (2000) GLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. Proc Natl Acad Sci USA 97:7313–7318PubMedCrossRefGoogle Scholar
  176. 176.
    Wyman A, Pinto AB, Sheridan R, Moley KH (2008) One-cell zygote transfer from diabetic to nondiabetic mouse results in congenital malformations and growth retardation in offspring. Endocrinology 149:466–469PubMedCrossRefGoogle Scholar
  177. 177.
    Gilman AG, Goodman LS, Gilman A (1980) The pharmacological basis of therapeutics. Macmillan, New YorkGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • James H. ChappellJr.
    • 1
  • Xiao Dan Wang
    • 1
  • Mary R. Loeken
    • 1
  1. 1.Section on Developmental and Stem Cell BiologyJoslin Diabetes CenterBostonUSA

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