Polymorphic susceptibility to the molecular causes of neural tube defects during diabetic embryopathy.
Previously, we demonstrated that neural tube defects (NTDs) are significantly increased in a mouse model of diabetic pregnancy. In addition, expression of Pax-3, a gene encoding a transcription factor required for neural tube development, is significantly decreased. This suggests that diabetic embryopathy results from impaired expression of genes regulating essential morphogenetic processes. Here, we report that in one mouse strain, C57Bl/6J, embryos are resistant to the effects of maternal diabetes on NTDs and Pax-3 expression, in contrast to a susceptible strain, FVB, in which maternal diabetes significantly increases NTDs (P = 0.02) and inhibits Pax-3 expression (P = 0.01). Resistance to NTDs caused by diabetic pregnancy is a dominant trait, as demonstrated by heterozygous embryos of diabetic or nondiabetic mothers of either strain. There was no significant difference between strains in expression of genes that regulate free radical scavenging pathways, suggesting that susceptibility to oxidative stress does not account for the genetic differences. Understanding the genetic bases for differential susceptibility to altered gene expression and NTDs in diabetic mice may be important in delineating the mechanisms by which maternal hyperglycemia interferes with embryo gene expression. Moreover, if susceptibility to diabetic embryopathy is variable in humans as well as in mice, it may be possible to screen individuals at increased risk for this complication of diabetes.
Section on Cellular and Molecular Physiology, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Lydie
L
Pani
Melissa
M
Horal
Mary R
MR
Loeken
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000502:physiology; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000209:etiology / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011110:Polymorphism, Genetic / Q000502:physiology*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000150:complications / Q000196:embryology*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse