Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-Induced injury

Mutation in the Nurr1 gene, a member of the nuclear receptor superfamily, c auses selective agenesis of dopaminergic neurons in the midbrain of null mi ce. Homozygous Nurr1 knockout mice (Nurr1-/-) die 1 day after birth, but he terozygous mice (Nurr1+/-) survive postnatally without obvious locomotor de ficits. Although adult Nurr1+/- mice show significantly reduced Nurr1 prote in levels in the substantia nigra (SN), they display a normal range of tyro sine hydroxylase-positive neuron numbers in the SN and normal levels of dop amine in the striatum. The reduction in Nurr1 expression in Nurr1+/- mice, however, confers increased vulnerability to the selective dopaminergic neur otoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compared with wi ld-type (Nurr1+/+) mice. This study suggests that Nurr1 may play an importa nt role in maintaining mature mesencephalic dopaminergic neuron function an d that a defect in Nurr1 may increase susceptibility to SN injury.