Altered cerebral thyroid hormone, WNT and NOTCH signalling and impaired myelination following intrauterine growth restriction in rats

Intrauterine growth restriction (IUGR) is associated with impaired brain development, including hypomyelination. Preclinical studies suggest that reduced myelination in IUGR may result from delayed oligodendrocyte maturation, but the mechanisms remain unclear. We examined whether altered expression of positive (thyroid hormone, TH) and negative (WNT and NOTCH signalling) regulators of oligodendrocyte maturation and myelination contribute to this delay. We induced IUGR in pregnant rats via bilateral uterine vessel ligation at embryonic day 18; sham surgeries generated controls. At postnatal day (P) 7, P14, and P35, we assessed oligodendrocytes (Olig2, APC) and myelinated fibres (MBP) by immunostaining, and measured expression of TH-related and WNT/NOTCH pathway genes using RT-qPCR in the cerebral white matter (P7 and P14 only). We found that IUGR offspring exhibited reduced MBP-immunoreactivity in the corpus callosum (P7) and external capsule (P7 and P14), and decreased density of APC-positive oligodendrocytes at P14. No difference in these measures were observed at P35, nor in the density of Olig2-positive cells at any age. At P7, IUGR brains showed increased Tcf4, Delta1 and Hes5 expression (WNT/NOTCH), and reduced Mct8, Oatp1c1, Dio1, and Dio3 mRNA expression (TH signalling), which were not different between groups by P14. Reductions in Mct8 mRNA expression were confirmed by immunohistochemical analysis. Our findings suggest that alteration of TH, WNT, and NOTCH signalling may be associated with impaired oligodendrocyte maturation and myelination in IUGR, providing insight into the mechanisms underlying white matter injury in IUGR infants.