Abstract
Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies.
Highlights
Failure to close the neural tube results in birth defects[1,2], with severity ranging from asymptomatic spina bifida occulta and surgically correctable cases of spina bifida to lethal conditions like exencephaly and anencephaly
We here report that periconceptional supplementation with folinic acid in Non-Obese Diabetic (NOD) diabetic dams reduced neural tube defects (NTDs) incidence from 40.2% to 21% (p = 0 .006, Supplemental Fig. 1)
To test whether protrusions were unique to the NOD strain, we induced hyperglycemia in females of the FVB strain with Streptozotocin[18], resulting in an NTD incidence of 21.6%19
Summary
Tube Closure in the Non-Obese received: 13 July 2015 accepted: 21 October 2015 Published: 23 November 2015. Of diabetes-exposed E8.5 embryos of the FVB strain (Fig. 6c), which could explain the higher incidence of protrusions in the NOD model compared to FVB These results demonstrate that the culture conditions, including supportive extracellular matrix and growth factors present in fetal calf serum, are not sufficient to rescue the cell migration deficiencies during the 26 hours of culture of the explants. In the NOD strain, NTD incidence is reduced by supplementation of folinic acid, as shown above, similar to the beneficial effects of folic acid in STZ-induced diabetic mouse pregnancies[58] These findings support the conclusion that metabolic factors can affect mesoderm formation and migration, and -together with the results from our molecular analyses- identify novel cellular and molecular targets for the prevention of neural tube and other birth defects. Our discovery of aberrant mesoderm migration during gastrulation in two different mouse models of Type I diabetes provides a unifying cellular mechanism that can explain both the developmental timing and the morphogenetic origin of the most common structural anomalies in diabetic embryopathy
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