Diabetic Pregnancies and Gastrulation



 DESCRIPTION (provided by applicant): Neurulation, the developmental process to form the neural tube, represents a critical, yet highly complex step in development of the nervous system. Deficiencies of this morphogenetic process can lead to neural tube defects, one of the most disabling birth defects in humans. One leading cause for neural tube defects is maternal diabetes during pregnancy, with an up to 10-fold higher risk, leading to the prevailing view that maternal diabetes disturbs the process of neural tube closure. However, results from our recent studies prompt us to posit a different hypothesis on the teratogenic mechanism: Maternal diabetes causes birth defects by affecting the process of gastrulation. We suggest that the teratogenicity occurs prior to neurulation, and that maternal diabetes, through the actions of genes such as Nodal, T, Wnt3a, Fgf8, and Tbx6, leads to an aberrant gastrulation process, commencing in the generation of ectopic mesodermal cells. With respect to neural tube defects, we propose that it is the presence of these cells that disrupts the process of neural tube closure. We believe this represents a paradigm shift away from the general concept of fuel-mediated teratogenesis towards a molecular signaling process that not only controls specific cellular properties, but has the potential to explain why neurulation defects usually only affect a small region of the neural tube. Furthermore, a gastrulation-based teratogenic mechanism can explain not only neural tube defects, but also the -seemingly disparate- deficiencies of the heart, and of the caudal region, that comprise the spectrum of defects known as diabetic embryopathy. Specifically, we will combine maternal and in vitro glucose modulation, quantitative assessment of primitive streak explants in culture, and next generation sequencing technology to determine how maternal diabetes and maternal blood glucose can (i) affect the capability of mesodermal cells to migrate and clear the primitive streak; (iii) alter the engagement of gene regulatory networks that are crucial for gastrulation; and (iii) act on migratory properties under conditions f supplementation with folate, which we show can ameliorate neural tube defect incidence in diabetic pregnancies of the Non Obese Diabetic strain of mice that serves as the model system for these studies. We expect that a successful completion of this project will lead to a new perspective on the teratogenicity of maternal diabetes during pregnancy, and to a significant and sustained impact on the field.