The aim of the present study was to investigate the putative cooperative
effects of transforming growth factor β (TGF-β) and glial cell line-derived
neurotrophic factor (GDNF) family ligands in the differentiation of midbrain progenitors
toward a dopaminergic phenotype. Therefore, a mouse midbrain embryonic day (E)
12 neurospheres culture was used as an experimental model. We show that
neurturin and persephin (PSPN), but not GDNF, are capable of transient
induction of dopaminergic neurons in vitro. This process, however, requires the
presence of endogenous TGF-β. In contrast, after 8 days in vitro GDNF rescued
the TGF-β neutralization-dependent loss of the TH-positive cells. In vivo, at
E14.5, no apparent phenotype concerning dopaminergic neurons was observed in Tgf-β2−/−/gdnf−/−
double mutant mice. In vitro, combined TGF-β/PSPN treatment achieved a yield of
approximately 20% TH-positive cells that were less vulnerable against
1-methyl-4-phenyl pyridinium ion toxicity. The underlying TGF-β/PSPN
differentiation signaling is receptor-mediated, involving p38 mitogen-activated
protein kinase and phosphatidylinositol 3-kinase pathways. These results
indicate that phenotype induction and survival of fully differentiated neurons
are accomplished through distinct pathways and individual factor requirement.
TGF-β is required for the induction of dopaminergic neurons, whereas GDNF is
required for regulating and/or maintaining a differentiated neuronal phenotype.
Moreover, this study suggests that the combination of TGF-β with PSPN is a
potent inductive cocktail for the generation of dopaminergic neurons that
should be considered in tissue engineering and cell replacement therapies for
Parkinson's disease.
Disclosure of potential conflicts of interest is found at the end of this article.
Attachment | Size |
---|---|
Transforming_Growth_Factor_Beta_Cooperates_With_Persephin_for_Dopaminergic_Phenotype_Induction.pdf | 2.06 MB |