Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-26T08:42:47.418Z Has data issue: false hasContentIssue false
  • English
  • Français

Genes, folate and homocysteine in embryonic development

Published online by Cambridge University Press:  28 August 2007

Thomas H. Rosenquist  and
Richard H. Finnell
Thomas H. Rosenquist*
Affiliation:
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198–6395, USA
Richard H. Finnell
Affiliation:
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198–6395, USA Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, NE 68198–6395, USA
*
*Corresponding author: Professor Thomas H. Rosenquist, fax +1 402 559 3990, email throsenq@unmc.edu
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Population-based studies of human pregnancies show that periconceptional folate supplementation has a significant protective effect for embryos during early development, resulting in a significant reduction in developmental defects of the face, the neural tube, and the cono-truncal region of the heart. These results have been supported by experiments with animal models. An obvious quality held in common by these three anatomical regions is that the normal development of each region depends on a set of multi-potent cells that originate in the mid-dorsal region of the neural epithelium. However, the reason for the sensitive dependence of these particular cells on folic acid for normal development has not been obvious, and there is no consensus about the biological basis of the dramatic rescue with periconceptional folate supplementation. There are two principal hypotheses for the impact of folate insufficiency on development; each of these hypotheses has a micronutrient component and a genetic component. In the first hypothesis the effect of low folate is direct, limiting the availability of folic acid to cells within the embryo itself; thus compromising normal function and limiting proliferation. The second hypothetical effect is indirect: low folate disrupts methionine metabolism; homocysteine increases in the maternal serum; homocysteine induces abnormal development by inhibiting the function of N-methyl-D-aspartate (NMDA) receptors in the neural epithelium. There are three general families of genes whose level of expression may need to be considered in the context of these two related hypotheses: folate-receptor genes; genes that regulate methionine– homocysteine metabolism; NMDA-receptor genes.

Keywords

GenesFolateHomocysteineEmbryonic developmental defects
Type
Micronutrient and Reprod. and Dev. Grps Sym. on relative contribution of diet and genotype to dev.
Information
Proceedings of the Nutrition Society , Volume 60 , Issue 1 , February 2001 , pp. 53 - 61
Copyright
Copyright © The Nutrition Society 2001

References

Andaloro, VJ, Monaghan, DT & Rosenquist, TH (1998) Dextromethorphan and other N-methyl D-asparate receptor antagonists are teratogenic in the avian embryo model. Pediatrics Research 43, 1–7.CrossRefGoogle Scholar
Barber, RC, Shaw, GM, Lammer, EJ, Greer, KA, Lacey, SW, Wasserman, CR & Finnell, RH (1998) Lack of association between mutations in the folate receptor alpha gene and spina bifida. American Journal of Medical Genetics 76, 310–317.Google Scholar
Barber, RC, Van Waes, JG, Lammer, EJ, Shaw, GM, Rosenquist, TH & Finnell, RH (2000) Folic acid and homocysteine and risk factors for neural tube defects. In Folate and Human Development [Massaro, EJ, editor]. Totowa, NJ: Humana Press (In the Press).Google Scholar
Bhave, SV, Snell, LD, Tabakoff, B & Hoffman, PL (1996) Mechanism of ethanol inhibition of NMDA receptor function in primary cultures of cerebral cortical cells. Alcoholism, Clinical and Experimental Research 20, 934–941.CrossRefGoogle ScholarPubMed
Bockman, DE, Redmond, ME & Kirby, ML (1990) Altered development of pharyngeal arch vessels after neural crest ablation. Annals of the New York Academy of Sciences 588, 296–304.CrossRefGoogle ScholarPubMed
Botto, LD, Khoury, MJ, Mulinare, J & Erickson, JD (1996) Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 98, 911–917.Google Scholar
Botto, LD & Mastroiacovo, P (1998) Exploring gene-gene interactions in the etiology of neural tube defects. Clinical Genetics 53, 456–459.CrossRefGoogle ScholarPubMed
Botto, LD & Yang, Q (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. American Journal of Epidemiology 151, 862–877.Google Scholar
Brody, LC, Baker, PJ, Chines, PS, Musick, A, Molloy, AM, Swanson, DA, Kirke, PN, Ghosh, S, Scott, M & Mills, JL (1999) Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects. Molecular Genetics Metabolism 67, 324–333.CrossRefGoogle ScholarPubMed
Brown, JC, Rosenquist, TH, & Monaghan, DT (1998) ERK2 activation by homocysteine in vascular smooth muscle cells. Biochemical and Biophysical Research Communications 251, 669–676.CrossRefGoogle ScholarPubMed
Christensen, B, Arbour, L, Tran, P, Leclerc, D, Sabbaghian, N, Platt, R, Gilfix, BM, Rosenblatt, DS, Gravel, RA, Forbes, P & Rozen, R (1999) Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. American Journal of Medical Genetics 84, 151–157.Google Scholar
Cornell-Bell, AH, Thomas, PG & Smith, SJ (1990) The excitatory neurotransmitter glutamate causes filopodia formation in cultured hippocampal astrocytes. Glia 3, 322–324.Google Scholar
Czeizel, A & Rode, K (1984) Trial to prevent first occurrence of neural tube defects by periconceptional multivitamin supplementation (letter). Lancet ii, 40.Google Scholar
Czeizel, AE, Toth, M & Rockenbauer, M (1996) Population-based case control study of folic acid supplementation during pregnancy. Teratology 53, 345–351.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Eskes, TK (1998) Open or closed? A world of difference: a history of homocysteine research. Nutrition Reviews 56, 236–244.Google Scholar
Ferencz, C, Loffredo, CA, Correa, Villaseñor & Wilson, PD (editors) (1997) Perspectives in Pediatric Cardiology, vol.5: Genetic and Environmental Risk Factors of Major Cardiac Malformations. The Baltimore–Washington Infant Study, 1981–1989. Armonk, NY: Futura Publishing Co. Inc. Google Scholar
Finnell, RH, Shaw, GM, Greer, KA, Barber, RC & Lammer, EJ (1998) Folate receptors and neural tube defects with special emphasis on craniofacial development. Critical Reviews in Oral Biology and Medicine 9, 38–53.CrossRefGoogle Scholar
Finnell, RH, Wlordarczyk, BC, Craig, JC, Piedrahita, JA & Bennett, GD (1997) Strain dependent alterations in the expression of folate pathway genes following teratogenic exposure to valproic acid in a mouse model. American Journal of Medical Genetics 70, 303–311.3.0.CO;2-P>CrossRefGoogle ScholarPubMed
Gofflot, F, van Maele Fabry, G & Picard, JJ (1996) Cranial nerves and ganglia are altered after in vitro treatment of mouse embryos with valproic acid (VPA) and 4-en-VPA. Developmental Brain Research 93, 62–69.Google Scholar
Graham, A, Koentges, G & Lumsden, A (1996) Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death. Molecular and Cellular Neuroscience 8, 76–83.Google Scholar
Graham, A & Lumsden, A (1996) Patterning the neural crest. Biochemical Society Symposia 62, 77–83.Google ScholarPubMed
Harmon, DL, Woodside, JV, Yarnell, JW, McMaster, D, Young, IS, McCrum, EE, Gey, KF, Whitehead, AS & Evans, AE (1996) The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. Quarterly Journal of Medicine 89, 571–577.Google Scholar
Hundt, W, Danysz, W, Holter, SM & Spanagel, R (1998) Ethanol and N-methyl-D-aspartate receptor complex interactions: a detailed drug discrimination study in the rat. Psychopharmacology (Berlin) 135, 44–51.Google Scholar
Johnson, VP, Swayze, VW II, Sato, Y & Andreasen, NC (1996) Fetal alcohol syndrome: craniofacial and central nervous system manifestations. American Journal of Medical Genetics 61, 329–339.Google Scholar
Kapusta, L, Haagmans, ML, Steegers, EA, Cuypers, MH, Blom, HJ & Eskes, TK (1999) Congenital heart defects and maternal derangement of homocysteine metabolism. Journal of Pediatrics 135, 773–774.CrossRefGoogle ScholarPubMed
Kirby, ML, Gale, TF & Stewart, DE (1983) Neural crest cells contribute to normal aorticopulmonary septation. Science 220, 1059–1061.CrossRefGoogle ScholarPubMed
Kirby, ML & Waldo, KL (1990) Role of neural crest in congenital heart disease. Circulation 82, 332–340.Google Scholar
Kirby, ML & Waldo, KL (1995) Neural crest and cardiovascular patterning. Circulation Research 77, 211–215.Google Scholar
Komuro, H & Rakic, P (1993) Modulation of neuronal migration by NMDA receptors. Science 260, 95–97.Google Scholar
Lipton, SA, Kim, WK, Choi, YB, Kumar, S, D'Emilia, DM, Rayudu, PV, Arnelle, DR & Stamler, JS (1997) Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proceedings of the National Academy of Sciences USA 94, 5923–5928.CrossRefGoogle ScholarPubMed
Mills, JL, Kirke, PN, Molloy, AM, Burke, H, Conley, MR, Lee, YJ, Mayne, PD, Weir, DG & Scott, JM (1999) Methylenetetrahydrofolate reductase thermolabile variant and oral clefts. American Journal of Medical Genetics 86, 71–74.3.0.CO;2-Y>CrossRefGoogle ScholarPubMed
Monaghan, DT, Andaloro, VJ & Skifter, DA (1998) Molecular determinants of NMDA receptor pharmacological diversity. Progress in Brain Research 116, 171–190.CrossRefGoogle ScholarPubMed
Morrison, K, Papapetrou, C, Hol, FA, Mariman, EC, Lynch, SA, Burn, J & Edwards, YH (1998) Susceptibility to spina bifida; an association study of five candidate genes. Annals of Human Genetics 62, 379–396.Google Scholar
Munger, RG, Romitti, PA, Daack Hirsch, S, Burns, TL, Murray, JC & Hanson, J (1996) Maternal alcohol use and risk of orofacial cleft birth defects. Teratology 54, 27–33.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
Nau, H (1985) Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicology and Applied Pharmacology 80, 243–250.CrossRefGoogle ScholarPubMed
Noden, DM (1975) An analysis of migratory behavior of avian cephalic neural crest cells. Developmental Biology 42, 106–130.CrossRefGoogle ScholarPubMed
Noden, DM (1978 a) The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Developmental Biology 67, 296–312.Google Scholar
Noden, DM (1978 b) The control of avian cephalic neural crest cytodifferentiation. II. Neural tissues. Developmental Biology 67, 313–329.Google Scholar
Noden, DM (1983) The embryonic origins of avian cephalic and cervical muscles and associated connective tissues. American Journal of Anatomy 68, 257–276.CrossRefGoogle Scholar
Ou, CY, Stevenson, RE, Brown, VK, Schwartz, CE, Allen, WP, Khoury, MJ, Rozen, R, Oakley, GP Jr & Adams, MJ Jr (1996) 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. American Journal of Medical Genetics 63, 610–614.Google Scholar
Piedrahita, JA, Oetama, B, Bennett, GD, Van Waes, J, Lacey, SW, Kamen, BA, Richardson, JA, Anderson, RG & Finnell, RH (1999) Mice lacking the folic acid-binding protein are defective in early embryonic development. Nature Genetics 23, 228–232.Google Scholar
Ramsbottom, D, Scott, JM, Molloy, A, Weir, DG, Kirke, PN, Mills, JL, Gallagher, PM & Whitehead, AS (1997) Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects? Clinical Genetics 51, 39–42.Google Scholar
Rashid, NA & Cambray-Deakin, MA (1992) N-methyl-D-aspartate effects on the growth, morphology and cytoskeleton of individual neurons in vitro. Brain Research 67, 301–308.Google Scholar
Rosenquist, TH & Beall, AC (1990 a) Elastogenic cells in the developing cardiovascular system: smooth muscle, non-muscle and cardiac neural crest. Annals of the New York Academy of Sciences 588, 106–119.Google Scholar
Rosenquist, TH, Beall, AC, Modis, L & Fishman, R (1990 b) Impaired elastic matrix development in the great arteries after ablation of the cardiac neural crest. Anatomical Record 226, 347–359.Google Scholar
Rosenquist, TH, Fray-Gavalas, CA, Waldo, K & Beall, AC (1990 c) Development of the musculoelastic septation complex in the avian truncus arteriosus. American Journal of Anatomy 180, 339–459.CrossRefGoogle Scholar
Rosenquist, TH, McCoy, JR, Waldo, K & Kirby, ML (1988) Origin and propagation of elastogenesis in the cardiovascular system. Anatomical Record 221, 860–871.CrossRefGoogle Scholar
Rosenquist, TH & Monaghan, DT (2000) Homocysteine and the NMDA receptor: Are they keys to conotruncal abnormalities? In Cardiovascular Development [Tomanek, R and Runyan, R, editors]. (In the Press).Google Scholar
Rosenquist, TH, Ratashak, SA & Selhub, J (1996) Homocysteine induces congenital heart and neural tube defects. Effect of folic acid. Proceedings of the National Academy of Sciences USA 93, 15227–15232.Google Scholar
Rosenquist, TH, Schneider, A & Monaghan, DT (1999) NMDA receptor agonists modulate homocysteine-induced developmental abnormalities. FASEB Journal 13, 1523–1531.CrossRefGoogle ScholarPubMed
Scherson, T, Serbedzija, G, Fraser, S & Bronner-Fraser, M (1993) Regulative capacity of the cranial neural tube to form neural crest. Development 118, 1049–1062.Google Scholar
Seller, MJ & Nevin, NC (1984) Periconceptional vitamin supplementation and the prevention of neural tube defects in South-East England and Northern Ireland. Journal of Medical Genetics 21, 325–330.Google Scholar
Shaw, GM, O'Malley, CD, Wasserman, CR, Tolarova, MM & Lammer, EJ (1995) Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. American Journal of Medical Genetics 59, 536–545.Google Scholar
Shaw, GM, Rozen, R, Finnell, RH, Todoroff, K & Lammer, EJ (1998) Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip. American Journal of Medical Genetics 80, 196–198.Google Scholar
Shaw, GM, Todoroff, K, Finnell, RH, Rozen, R & Lammer, EJ (1999) Maternal vitamin use, infant C677T mutation in MTHFR, and isolated cleft palate risk (letter). American Journal of Medical Genetics 85, 84–85.Google Scholar
Single, FN, Rozov, A, Burnashev, N, Zimmermann, F, Hanley, DF, Forrest, D, Curran, T, Jensen, V, Hvalby, O, Sprengel, R & Seeburg, PH (2000) Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R). Journal of Neuroscience 20, 2558–2566.CrossRefGoogle ScholarPubMed
Speer, MC, Nye, J, McLone, D, Worley, G, Melvin, EC, Viles, KD, Franklin, A, Drake, C, Mackey, J, & George, TM (1999) Possible interaction of genotypes at cystathionine beta-synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects. NTD Collaborative Group. Clinical Genetics 56, 142–144.CrossRefGoogle ScholarPubMed
Speer, MC, Worley, G, Mackey, JF, Melvin, E, Oakes, WJ & George, TM (1997) The NTD Collaborative Group. The thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) is not a major risk factor for neural tube defect in American Caucasians. Neurogenetics 1, 149–150.CrossRefGoogle Scholar
Steegers-Theunissen, RP, Boers, GH, Blom, HJ, Nijhuis, JG, Thomas, CM, Borm, GF & Eskes, TK (1995) Neural tube defects and elevated homocysteine levels in amniotic fluid. American Journal of Obstetrics and Gynecology 172, 1436–1441.Google Scholar
Steegers-Theunissen, RP, Boers, GH, Trijbels, FJ, Finkelstein, JD, Blom, HJ, Thomas, CM, Borm, GF, Wouters, MG & Eskes, TK (1994) Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism: Clinical and Experimental 43, 1475–1480.CrossRefGoogle ScholarPubMed
Steen, MT, Boddie, AM, Fisher, AJ, Macmahon, W, Saxe, D, Sullivan, KM, Dembure, PP & Elsas, LJ (1998) Neural-tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid. Prenatal Diagnosis 18, 545–555.3.0.CO;2-2>CrossRefGoogle ScholarPubMed
Thieszen, SL, Dalton, M, Gadson, PF, Patterson, E & Rosenquist, TH (1996) Embryonic lineage of vascular smooth muscle cells determines responses to collagen matrices and integrin receptor expression. Experimental Cell Research 227, 135–145.Google Scholar
Thieszen, SL & Rosenquist, TH (1995) Developmental regulation of decorin and collagen: implications for matrix pattern formation. Matrix Biology 14, 573–582.Google Scholar
Thomas, CM, Borm, GF, Wouters, MG & Eskes, TK (1994) Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism: Clinical and Experimental 43, 1475–1480.Google Scholar
Thomas, MP, Rosenquist, TH & Monaghan, DT (2000) Evidence for early developmental expression of NMDA receptors in chick embryos. FASEB Journal 14, A545.Google Scholar
Uberti, D, Belloni, M, Grilli, M, Spano, P & Memo, M (1998) Induction of tumour-suppressor phosphoprotein p53 in the apoptosis of cultured rat cerebellar neurones triggered by excitatory amino acids. European Journal of Neuroscience 10, 246–254.Google Scholar
van der Put, NM, Steegers-Theunissen, RP, Frosst, P, Trijbels, FJ, Eskes, TK, van den Heuvel, LP, Mariman, EC, den Heyer, M, Rozen, R & Blom, HJ (1995) Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 346, 1070–1071.Google Scholar
van der Put, NM, Thomas, CM, Eskes, TK, Trijbels, FJ, Steegers-Theunissen, RP, Mariman, EC, de Graaf Hess, A, Smeitink, JA & Blom, HJ (1997) Altered folate and vitamin B12 metabolism in families with spina bifida offspring. Quarterly Journal of Medicine 90, 505–510.CrossRefGoogle ScholarPubMed
Wafford, KA, Kathoria, M, Bain, CJ, Marshall, G, Le-Bourdelles, B, Kemp, JA & Whiting, PJ (1995) Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site. Molecular Pharmacology 47, 374–380.Google Scholar
Wald, NJ, Hackshaw, AD, Stone, R & Sourial, NA (1996) Blood folic acid and vitamin B12 in relation to neural tube defects. British Journal of Obstetric Gynecology 103, 319–324.Google Scholar
Wang, C, Pralong, WF, Schulz, MF, Rougon, G, Aubry, JM, Pagliusi, S, Robert, A & Kiss, JZ (1996) Functional N-methyl-D-asparate receptors in O-2A glial precursor cells: a critical role in regulating polysialic acid-neural cell adhesion molecule expression and cell migration. Journal of Cell Biology 135, 1565–1581.Google Scholar
Weil, M, Jacobson, MD & Ratt, MC (1997) Is programmed cell death required for neural tube closure? Current Biology 7, 281–284.Google Scholar
Wenzel, A, Fritschy, JM, Mohler, H & Benke, D (1997) NMDA receptor heterogeneity during postnatal development of the rat brain: differential expression of the NR2A, NR2B, and NR2C subunit proteins. Journal of Neurochemistry 68, 469–478.Google Scholar
Wilson, A, Platt, R, Wu, Q, Leclerc, D, Christensen, B, Yang, H, Gravel, RA & Rozen, RA (1999) Common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Molecular Genetics Metabolism 67, 317–323.Google Scholar
Winkler, A, Mahal, B, Kiianmaa, K, Zieglgansberger, W & Spanagel, R (1999) Effects of chronic alcohol consumption on the expression of different NR1 splice variants in the brain of AA and ANA lines of rats. Brain Research 72, 166–175.Google Scholar
Wood, MW, VanDongen, HM & VanDongen, AM (1999) A mutation in the glycine binding pocket of the N-methyl-d-aspartate receptor NR1 subunit alters agonist efficacy. Brain Research 73, 189–192.Google Scholar
Yates, JRW, Ferguson Smith, MA, Shenkin, A, Guzman-Rodriguez, R, White, M & Clark, BJ (1987) Is disordered folate metabolism the basis of the genetic predisposition to neural tube defects. Clinical Genetics 31, 219–238.Google Scholar