Figure 1

Signaling pathways involved in regulation of cellular survival and death by engrailed and Nurr1 in mesencephalic dopaminergic neurons. Transcriptional regulation of several survival/death-regulating genes including the pan-neurotrophin receptor P75 and protooncogene Ret, as well as modulation of downstream survival mechanisms, such as MAPK (Erk1/2) by engrailed and Nurr1 leads to the long-term regulation of survival and death of mesDA neurons. Down-regulation of P75 expression by the engrailed genes results in disinhibition of Erk1/2, resulting in survival of mesDA neurons. The effect is similar to the Ret-mediated activation of Erk1/2 by Nurr1. The survival and degeneration pathways regulated by engrailed and Nurr1 converge on mitochondria and are mediated by the anti- and pro-apoptotic members of the Bcl-2 family, Bcl2, Bcl-xL and Bax.