The Role of Transcription Factors in Regulating Adult Neurogenesis after Excitotoxic Brain Injury

Abstract

While compensatory striatal neurogenesis is well documented in many injury models, cells of the correct lineage for endogenous repair are not always regenerated. To understand why, the molecular profile of subventricular zone (SVZ)-derived neural progenitor cells (NPCs), and their response to injury was investigated. Expression of the transcription factors Mash1, Dlx2, Pax6 and Olig2 in transitamplifying- precursor cells (TAPs) and neuroblasts was examined following quinolinic acid (QA) lesioning of the adult rat striatum. It was demonstrated that TAPs responded to lesioning in a heterogeneous manner, with expansion particularly of the Dlx2+ subpopulation. Dlx2+ neuroblasts also increased at early time points compared to controls. Previous work identified SVZ-derived bipolar and multipolar cells within the lesioned striatum. I characterised and quantified migration and differentiation of retrovirally-labelled SVZ-derived green fluorescent protein (GFP) cells within the lesioned striatum. In addition to neuroblasts, migratory Olig2+ bipolar cells were observed, representing oligodendrocyte progenitor cells (OPCs). Multipolar cells also expressed NG2, indicating OPCs were recruited into the lesioned striatum. Proneural genes can repress Olig2 lineage cells, and substantially increase neurogenesis when overexpressed in the adult brain. Proneural Dlx2-GFP and Pax6-GFP retroviruses were injected into the SVZ on the day of lesioning, or two days post lesion (dpl), when the greatest migratory response was observed in controls. Surprisingly, Pax6 overexpression decreased striatal neurogenesis from NPCs born on the day of lesioning, but increased oligodendroglial cells from NPCs born two dpl. Dlx2 overexpression had no effect on NPC migration from cells born at the time of lesioning. However at two dpl, a non-neurogenic time point in controls, Dlx2 increased numbers of striatal neuroblasts and the percentage of neurogenic cells in the lesioned striatum. These results indicated preferential recruitment of Dlx2+ NPCs, GABAergic lineage precursors and the correct cell type for QA-induced striatal regeneration. However, retrovirallyoverexpressed proneural genes were downregulated within the lesioned striatum, suggesting factors secreted from injured areas could alter cell fate. Quantitative-PCR analysis of signalling genes confirmed multiple SVZ alterations after injury, some with the potential to increase oligodendrocytelineage signalling. Understanding molecular signals regulating lineage after injury is essential before regenerative medicine can progress towards successful therapies.