TY - JOUR
T1 - 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
AU - De Chevigny, Antoine
AU - Cooper, Oliver
AU - Vinuela, Angel
AU - Reske-Nielsen, Casper
AU - Lagace, Diane C.
AU - Eisch, Amelia J.
AU - Isacson, Ole
PY - 2008/9
Y1 - 2008/9
N2 - 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-Cre-ERT2/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.
AB - 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-Cre-ERT2/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.
KW - Adult neurogenesis
KW - Neuroblasts
KW - Parkinson's disease
KW - Striatum
KW - Subventricular zone
KW - Transforming growth factor α
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UR - http://www.scopus.com/inward/citedby.url?scp=55049134362&partnerID=8YFLogxK
U2 - 10.1634/stemcells.2008-0080
DO - 10.1634/stemcells.2008-0080
M3 - Article
C2 - 18556510
AN - SCOPUS:55049134362
SN - 1066-5099
VL - 26
SP - 2349
EP - 2360
JO - STEM CELLS
JF - STEM CELLS
IS - 9
ER -