Fate mapping and lineage analyses demonstrate the production of a large number of striatal neuroblasts after transforming growth factor alpha and noggin striatal infusions into the dopamine-depleted striatum.
Infusion of transforming growth factor alpha (TGFalpha) 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 TGFalpha 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 TGFalpha 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 TGFalpha 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-CreER(T2)/R26R-YFP mice that allow genetic fate-mapping of SVZ nestin(+) cells, we show that TGFalpha-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 TGFalpha 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.
Udall Parkinson Disease Research Center of Excellence, Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.
Antoine
A
de Chevigny
Oliver
O
Cooper
Angel
A
Vinuela
Casper
C
Reske-Nielsen
Diane C
DC
Lagace
Amelia J
AJ
Eisch
Ole
O
Isacson
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism; D004298:Dopamine / Q000172:deficiency*; D000089662:Doublecortin Protein; D005260:Female; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D046569:Neuroepithelial Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D000099176:Noggin Protein
D002352:Carrier Proteins; D004298:Dopamine; D000089662:Doublecortin Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D000099176:Noggin Protein; C000714848:Dcx protein, rat; C577485:Nes protein, mouse; C577486:Nes protein, rat