The N-methyl-d-aspartate Receptor in Heart Development: a Gene Knockdown Model Using SiRNA

Overview

Journal Reprod Toxicol

Specialties Reproductive Medicine
Toxicology

Date 2009 Sep 10

PMID 19737608

Citations 3

Authors

Octavian V Lie

Gregory D Bennett

Thomas H Rosenquist

Affiliations

Soon will be listed here.

Abstract

Antagonists of the N-methyl-d-aspartate receptor (NMDAR) may disrupt the development of the cardiac neural crest (CNC) and contribute to conotruncal heart defects. To test this interaction, a loss-of-function model was generated using small interfering RNAs (siRNA) directed against the critical NR1-subunit of this receptor in avian embryos. The coding sequence of the chicken NR1 gene and predicted protein sequences were characterized and found to be homologous with other vertebrate species. Analysis of its spatiotemporal expression demonstrated its expression within the neural tube at pre-migratory CNC sites. siRNA targeted to the NR1-mRNA in pre-migratory CNC lead to a significant decrease in NR1 protein expression. However, embryo survival and heart development were not adversely affected. These results indicate that the CNC may function normally in the absence of functional NMDAR, and that NMDAR antagonists may have a complex impact upon the CNC that transcends impairment of a single receptor type.

Citing Articles

[Maternal gene polymorphisms and their interactions with periconceptional folic acid supplementation in relation to offspring ventricular septal defects].

Ruan X, Sun M, Wei J, Luo M, Liu H, Tang J Zhongguo Dang Dai Er Ke Za Zhi. 2024; 26(9):899-906.

PMID: 39267503 PMC: 11404469. DOI: 10.7499/j.issn.1008-8830.2403067.

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia.

Liu Y, Luo Z, Liao Z, Wang M, Zhou Y, Luo S Front Cardiovasc Med. 2022; 9:837142.

PMID: 35498024 PMC: 9039344. DOI: 10.3389/fcvm.2022.837142.

NMDA-R inhibition affects cellular process formation in Tilapia melanocytes; a model for pigmented adrenergic neurons in process formation and retraction.

Ogundele O, Okunnuga A, Fabiyi T, Olajide O, Akinrinade I, Adeniyi P Metab Brain Dis. 2013; 29(2):541-51.

PMID: 24242214 DOI: 10.1007/s11011-013-9447-6.

References

van Driel L, de Jonge R, Helbing W, van Zelst B, Ottenkamp J, Steegers E . Maternal global methylation status and risk of congenital heart diseases. Obstet Gynecol. 2008; 112(2 Pt 1):277-83. DOI: 10.1097/AOG.0b013e31817dd058. View

Waldo K, Hutson M, Stadt H, Zdanowicz M, Zdanowicz J, Kirby M . Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field. Dev Biol. 2005; 281(1):66-77. DOI: 10.1016/j.ydbio.2005.02.011. View

Xiu X, Zhang S, Lu X, Liang M, Yu J, Hou J . [SiRNA inhibition of E6AP expression in cervical cancer cells]. Zhonghua Bing Li Xue Za Zhi. 2009; 37(12):822-5. View

Zaidi A, Enomoto H, Milbrandt J, Roth K . Dual fluorescent in situ hybridization and immunohistochemical detection with tyramide signal amplification. J Histochem Cytochem. 2000; 48(10):1369-75. DOI: 10.1177/002215540004801007. View

Shaw G, OMalley C, Wasserman C, Tolarova M, Lammer E . Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet. 1995; 59(4):536-45. DOI: 10.1002/ajmg.1320590428. View

Hoffman J . Incidence of congenital heart disease: I. Postnatal incidence. Pediatr Cardiol. 1995; 16(3):103-13. DOI: 10.1007/BF00801907. View

Kapusta L, Haagmans M, Steegers E, Cuypers M, Blom H, Eskes T . Congenital heart defects and maternal derangement of homocysteine metabolism. J Pediatr. 1999; 135(6):773-4. DOI: 10.1016/s0022-3476(99)70102-2. View

Cull-Candy S, Leszkiewicz D . Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004; 2004(255):re16. DOI: 10.1126/stke.2552004re16. View

Hardingham G, Fukunaga Y, Bading H . Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002; 5(5):405-14. DOI: 10.1038/nn835. View

10.

Eberhart J, Swartz M, Koblar S, Pasquale E, Krull C . EphA4 constitutes a population-specific guidance cue for motor neurons. Dev Biol. 2002; 247(1):89-101. DOI: 10.1006/dbio.2002.0695. View

11.

Srivastava S, Chandrasekar B, Gu Y, Luo J, Hamid T, Hill B . Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res. 2007; 74(3):445-55. DOI: 10.1016/j.cardiores.2007.02.016. View

12.

Mulinare J, Cordero J, Erickson J, Berry R . Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA. 1988; 260(21):3141-5. View

13.

Zarain-Herzberg A, Lee-Rivera I, Rodriguez G, Lopez-Colome A . Cloning and characterization of the chick NMDA receptor subunit-1 gene. Brain Res Mol Brain Res. 2005; 137(1-2):235-51. DOI: 10.1016/j.molbrainres.2005.03.006. View

14.

Brauer P, Rosenquist T . Effect of elevated homocysteine on cardiac neural crest migration in vitro. Dev Dyn. 2002; 224(2):222-30. DOI: 10.1002/dvdy.10105. View

15.

Hamburger V, HAMILTON H . A series of normal stages in the development of the chick embryo. J Morphol. 2014; 88(1):49-92. View

16.

Salahpour A, Medvedev I, Beaulieu J, Gainetdinov R, Caron M . Local knockdown of genes in the brain using small interfering RNA: a phenotypic comparison with knockout animals. Biol Psychiatry. 2006; 61(1):65-9. DOI: 10.1016/j.biopsych.2006.03.020. View

17.

Paupard M, Friedman L, Zukin R . Developmental regulation and cell-specific expression of N-methyl-D-aspartate receptor splice variants in rat hippocampus. Neuroscience. 1997; 79(2):399-409. DOI: 10.1016/s0306-4522(96)00677-x. View

18.

Lipton S, Kim W, Choi Y, Kumar S, DEmilia D, Rayudu P . Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997; 94(11):5923-8. PMC: 20882. DOI: 10.1073/pnas.94.11.5923. View

19.

Wyszynski D, Diehl S . Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and risk of nonsyndromic cleft lip. Am J Med Genet. 2000; 92(1):79-80. DOI: 10.1002/(sici)1096-8628(20000501)92:1<79::aid-ajmg14>3.0.co;2-h. View

20.

Chen Y, Krull C, Reneker L . Targeted gene expression in the chicken eye by in ovo electroporation. Mol Vis. 2004; 10:874-83. View