Effect of Maternal Hyperglycemia on Cortical Neuronal Migration: Hypofunction of Reelin Signaling

Maternal diabetes increases the risk of neurodevelopmental alterations in the offspring, yet the molecular links to early corticogenesis remain unclear. During corticogenesis, radial migration is a coordinated process regulated by Reelin signaling and its disruption has been associated with abnormal cortical patterning. We reanalyze dorsal telencephalon transcriptomes from embryonic day 12 (E12) non-neural tube-defect rat embryos to identify canonical pathways perturbed by maternal hyperglycemia.

Gene expression profiles from the dorsal prosencephalon at E12 from control and streptozotocin-treated dams (50 mg/kg at E5.5) were interrogated with Ingenuity Pathway Analysis (IPA). We then assessed Reelin pathway components using quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunohistochemistry, and immunoblotting at E12 and E16, and examined postnatal cytoarchitecture/morphology in the primary motor cortex (M1) at postnatal day zero (P0) and P21 using hematoxylin-eosin and Golgi-Cox staining. All analyses excluded embryos with neural tube defects (NTD) to avoid cofounding by gross malformations.

IPA revealed Reelin signaling in neurons as the only canonical pathway with a non-zero activation z-score, predicting inhibition in E12 embryos from diabetic rats. Concordantly, protein levels of Reelin (RELN), apolipoprotein E receptor 2/low-density lipoprotein receptor-related protein 8 (ApoER2/LRP8), very low-density lipoprotein receptor (VLDLR), and Disabled Homolog 1 (DAB1) were reduced at E12/E16 (all p < 0.05). N-cadherin (N-CAD) showed disrupted radial localization along the ventricular-pial axis despite unchanged total abundance, consistent with impaired neuron-radial glia adhesion/polarity. Postnatally, the M1 showed increased layer I cellularity, ectopic pyramidal neurons, and aberrant laminar organization.

Maternal hyperglycemia is associated with attenuation of the Reelin signaling pathway and N-CAD mislocalization, providing a mechanistic framework for defective neuronal migration and abnormal lamination that persist into early postnatal life. Focusing on NTD-negative embryos isolates the pathway-specific effects of maternal hyperglycemia and nominates Reelin-pathway hypofunction as a candidate driver of altered fetal cortical patterning.