Use of a Murine Embryonic Stem Cell Line That is Sensitive to High Glucose Environment to Model Neural Tube Development in Diabetic Pregnancy

Overview

Journal Birth Defects Res A Clin Mol Teratol

Publisher Wiley

Date 2014 Aug 16

PMID 25124397

Citations 4

Authors

Kaitlyn Sanders

Jin Hyuk Jung

Mary R Loeken

Affiliations

Soon will be listed here.

Abstract

Background: Neural tube defects (NTDs) are significantly increased by maternal diabetes. Embryonic stem cells (ESC) that can differentiate into neuroepithelium and can sense supraphysiological glucose concentrations would be very valuable to simulate the effects of maternal diabetes on molecular and cellular processes during neural tube formation.

Methods: LG-ESC, a recently established ESC line that expresses the glucose transporter, Scl2a2, and is sensitive to elevated glucose concentrations, were grown for up to 8 days in a three-dimensional culture to form neural cysts. We tested whether high glucose media inhibits expression of Pax3, a gene that is required for neural tube closure and whose expression is inhibited in embryos of diabetic mice, and inhibits formation of neural cysts.

Results: Pax3 expression was detected after 4 days of culture and increased with time. Pax3 expression was inhibited by high glucose media, but not if cells had been cultured in low glucose media for the first 4 days of culture. Pax7, which is also expressed in dorsal neural tube, was not detected. Pax6, which is expressed in the ventral neural tube, was detected only after 8 days of culture, but was not inhibited by high glucose. High glucose media did not inhibit formation of neural cysts.

Conclusion: LG-ESC can be used as a model of embryonic exposure to a diabetic environment during neural tube development. While high glucose exposure inhibits expression of a gene required for neural tube closure, it may not inhibit all of the processes involved in formation of a neural tube-like structure.

Citing Articles

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References

Chang T, Horal M, Jain S, Wang F, Patel R, Loeken M . Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia. 2003; 46(4):538-45. DOI: 10.1007/s00125-003-1063-2. View

Wei D, Loeken M . Increased DNA methyltransferase 3b (Dnmt3b)-mediated CpG island methylation stimulated by oxidative stress inhibits expression of a gene required for neural tube and neural crest development in diabetic pregnancy. Diabetes. 2014; 63(10):3512-22. PMC: 4171658. DOI: 10.2337/db14-0231. View

Viana M, Herrera E, Bonet B . Teratogenic effects of diabetes mellitus in the rat. Prevention by vitamin E. Diabetologia. 1996; 39(9):1041-6. DOI: 10.1007/BF00400652. View

Wallingford J . Planar cell polarity and the developmental control of cell behavior in vertebrate embryos. Annu Rev Cell Dev Biol. 2012; 28:627-53. DOI: 10.1146/annurev-cellbio-092910-154208. View

Pantaleon M, Harvey M, Pascoe W, James D, Kaye P . Glucose transporter GLUT3: ontogeny, targeting, and role in the mouse blastocyst. Proc Natl Acad Sci U S A. 1997; 94(8):3795-800. PMC: 20520. DOI: 10.1073/pnas.94.8.3795. View

Pani L, Horal M, Loeken M . 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. 2002; 16(6):676-80. PMC: 155364. DOI: 10.1101/gad.969302. View

Reece E, Eriksson U . The pathogenesis of diabetes-associated congenital malformations. Obstet Gynecol Clin North Am. 1996; 23(1):29-45. DOI: 10.1016/s0889-8545(05)70243-6. View

Gareskog M, Cederberg J, Eriksson U, Wentzel P . Maternal diabetes in vivo and high glucose concentration in vitro increases apoptosis in rat embryos. Reprod Toxicol. 2006; 23(1):63-74. DOI: 10.1016/j.reprotox.2006.08.009. View

Yang P, Zhao Z, Reece E . Activation of oxidative stress signaling that is implicated in apoptosis with a mouse model of diabetic embryopathy. Am J Obstet Gynecol. 2008; 198(1):130.e1-7. DOI: 10.1016/j.ajog.2007.06.070. View

10.

Fine E, Horal M, Chang T, Fortin G, Loeken M . Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes. 1999; 48(12):2454-62. DOI: 10.2337/diabetes.48.12.2454. View

11.

Aghayan M, Rao L, Smith R, JARETT L, Charron M, Thorens B . Developmental expression and cellular localization of glucose transporter molecules during mouse preimplantation development. Development. 1992; 115(1):305-12. DOI: 10.1242/dev.115.1.305. View

12.

Hogan A, Heyner S, Charron M, Copeland N, Gilbert D, Jenkins N . Glucose transporter gene expression in early mouse embryos. Development. 1991; 113(1):363-72. DOI: 10.1242/dev.113.1.363. View

13.

Boroviak T, Loos R, Bertone P, Smith A, Nichols J . The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol. 2014; 16(6):516-28. PMC: 4878656. DOI: 10.1038/ncb2965. View

14.

Wang X, Morgan S, Loeken M . Pax3 stimulates p53 ubiquitination and degradation independent of transcription. PLoS One. 2012; 6(12):e29379. PMC: 3247257. DOI: 10.1371/journal.pone.0029379. View

15.

Ybot-Gonzalez P, Savery D, Gerrelli D, Signore M, Mitchell C, Faux C . Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development. 2007; 134(4):789-99. PMC: 1839770. DOI: 10.1242/dev.000380. View

16.

Jung J, Wang X, Loeken M . Mouse embryonic stem cells established in physiological-glucose media express the high KM Glut2 glucose transporter expressed by normal embryos. Stem Cells Transl Med. 2013; 2(12):929-34. PMC: 3841087. DOI: 10.5966/sctm.2013-0093. View

17.

Li R, Thorens B, Loeken M . 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. 2007; 50(3):682-9. DOI: 10.1007/s00125-006-0579-7. View

18.

Lee S, Lumelsky N, Studer L, Auerbach J, McKay R . Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol. 2000; 18(6):675-9. DOI: 10.1038/76536. View

19.

Pryor S, Massa V, Savery D, Greene N, Copp A . Convergent extension analysis in mouse whole embryo culture. Methods Mol Biol. 2012; 839:133-46. PMC: 3616368. DOI: 10.1007/978-1-61779-510-7_11. View

20.

Mansouri A, Stoykova A, Torres M, Gruss P . Dysgenesis of cephalic neural crest derivatives in Pax7-/- mutant mice. Development. 1996; 122(3):831-8. DOI: 10.1242/dev.122.3.831. View