Developmental origins and consequences of altered gliogenesis during brain sparing

Growth of the brain is often prioritized or spared over that of other fetal organs during intrauterine growth restriction (IUGR). This brain sparing is thought to be essential for fetal survival but it is also associated with postnatal neurodevelopmental defects and adult dysmyelination. Despite its importance, the cellular and molecular mechanisms linking fetal brain sparing to long-term alterations in the myelin-producing glia, oligodendrocytes (OLs), remain unclear. Using a mouse model of IUGR, my preliminary data identify a specific developmental delay in the onset of OL differentiation at fetal/neonatal stages. Surprisingly, this early delay becomes over-compensated at postnatal stages, with supernumerary pre-myelinating OLs (Pre-OLs) and a Pre-OL-to-OL imbalance correlating with an adult neocortical myelin deficit. The overarching goal of this proposal is to identify the cellular and molecular mechanisms by which IUGR changes the life-long development and function of the OL-lineage. To achieve this, I will combine malnutrition and placental deficiency models of IUGR in mice with transgenic methods, advanced imaging, single-nucleus transcriptomics and metabolomics. This mouse project will deliver a mechanistic understanding of the developmental origins of dysmyelination and provide useful new insights for future human studies of dysmyelination-associated neurodevelopmental disorders.