Netrin-1 Favors Neuroblast Lineage Plasticity in SVZ of Injured Neonatal Brain

Saturday, February 13, 2016
Stephanie Fox, Children's National Health System, Washington, DC
Infants born extremely preterm and with very low birthweight are susceptible to hypoxia-induced diffuse white matter injury (DWMI), leading to loss of oligodendrocytes, myelin abnormalities, and long-term behavioral disorders. Endogenous progenitor cells in the developing brain hold great potential for preventing or reversing DWMI caused by hypoxic events. Using a model of chronic hypoxia in the perinatal rodent, which produces DWMI analogous to the injury observed in preterm infants, we employed genetic lineage tracing to demonstrate that distinct progenitor/stem cell populations are capable of regenerating oligodendrocytes in white matter (WM) after injury. These populations include cells expressing Glial Fibrillary Acidic Protein (GFAP), Platelet Derived Growth Factor Receptor-α (PDGFRα), Ascl1 (Mash1), and Glutamate Decarboxylase-65 (GAD65). We go on to demonstrate a hypoxia-induced increase in the expression of chemotropic factor netrin-1 (NTN1) in both the subventricular zone (SVZ) and choroid plexus (CP). GAD65+ progenitors express NTN1 receptors including deleted in colorectal cancer (DCC), uncoordinated homolog 2 (Unc5H2) and Unc5H4. Using both in vivo and in vitro methods, we demonstrate a NTN1-mediated migratory effect on GAD65-expressing progenitors in the SVZ, resulting in an increase in GAD65-derived oligodendrocytes in the overlying WM. NTN1 also plays a role in lineage determination, as treating SVZ progenitors with NTN1 leads to generation of oligodendrocytes and astrocytes derived from GAD65-expressing cells. Our study demonstrates novel sources of glia in the developing brain following DWMI and reveals NTN1 to be a molecular signal associated with GAD65-progenitor migration and lineage plasticity in the postnatal brain.