Fate Mapping and Lineage Analyses Demonstrate the Production of a Large Number of Striatal Neuroblasts After Transforming Growth Factor α and Noggin Striatal Infusions into the Dopamine-Depleted Striatum

Abstract

Infusion of transforming growth factor α (TGFα) into the adult dopamine (DA)-depleted striatum generates a local population of nestin+/proliferating cell nuclear antigen (PCNA)+ newborn cells. The precise origin and fate of these new striatal cells are unknown, making it difficult to direct them for neural repair in Parkinson's disease. Experiments in rats using 5-bromo-2′-deoxyuridine (BrdU) to label neural progenitor cells showed that during TGFα infusion in the DA-depleted striatum, newborn striatal cells formed a homogeneous population of precursors, with the majority coexpressing nestin, Mash1, Olig2, and epidermal growth factor receptor, consistent with the phenotype of multipotent C cells. Upon TGFα pump withdrawal, the subventricular zone (SVZ) was repopulated by neuroblasts. Strikingly, during this period, numerous clusters of doublecortin+/polysialylated neuronal cell adhesion molecule+ neuroblasts were also produced in the ipsilateral medial striatum. In parallel, striatal BrdU+/glial fibrillary acidic protein+ astrocytes were generated, but no BrdU+/O4+/CNPase+ oligodendrocytes were generated. Infusion of the neuralizing bone morphogenetic protein antagonist noggin after TGFα pump withdrawal increased the neuroblast-to-astrocyte ratio among new striatal cells by blocking glial differentiation but did not alter striatal neurogenesis. At no time or treatment condition were differentiated neurons generated, including DA neurons. Using 6-hydroxydopamine-lesioned nestin-CreERT2/R26R-YFP mice that allow genetic fate-mapping of SVZ nestin+ cells, we show that TGFα-generated striatal cells originate from SVZ nestin+ precursors that confirmed data from the rats on the phenotype and fate of striatal nestin+/PCNA+ cells upon TGFα withdrawal. This work demonstrates that a large population of multipotent striatal C-like cells can be generated in the DA-depleted striatum that do not spontaneously differentiate into DA neurons.Disclosure of potential conflicts of interest is found at the end of this article.