Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons

Pitx3 is a critical homeodomain transcription factor for the proper development and survival of mesodiencephalic dopaminergic (mdDA) neurons in mammals. Several variants of this gene have been associated with human Parkinson's disease (PD), and lack of Pitx3 in mice causes thepreferentiallossofsubstantianigraparscompacta(SNc)mdDAneuronsthataremostaffectedinPD.ItiscurrentlyunclearhowPitx3activity promotes the survival of SNc mdDA neurons and which factors act upstream and downstream of Pitx3 in this context. Here we show that a transient expression of glial cell line-derived neurotrophic factor (GDNF) inthemurineventralmidbrain(VM)induces transcription of Pitx3 via NF-κB-mediated signaling, and that Pitx3 is in turn required for activating the expression of brain-derived neurotrophic factor (BDNF) in a rostrolateral (SNc) mdDA neuron subpopulation during embryogenesis. The loss of BDNF expression correlates with the increased apoptotic cell death of this mdDA neuronal subpopulation in Pitx3^-/-mice, whereas treatment ofVMcell cultures with BDNF augments the survival of the Pitx3^-/- mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell deathin theabsenceof Pitx3.As the feedforward regulation ofGDNF,Pitx3,andBDNFexpression also persists in the adult rodent brain,ourdata suggest that the disruption of the regulatory interactionbetweenthese three factors contributes to the loss ofmdDAneuronsin Pitx3^-/-mutant mice and perhaps also in human PD.