Fate of midbrain dopaminergic neurons controlled by the engrailed genes

Deficiencies in neurotransmitter-specific cell groups in the midbrain resul t in prominent neural disorders, including Parkinson's disease, which is ca used by the loss of dopaminergic neurons of the substantia nigra. We have i nvestigated in mice the role of the engrailed homeodomain transcription fac tors, En-1 and En-2, in controlling the developmental fate of midbrain dopa minergic neurons. En-1 is highly expressed by essentially all dopaminergic neurons in the substantia nigra and ventral tegmentum, whereas En-2 is high ly expressed by a subset of them. These neurons are generated and different iate their dopaminergic phenotype in En-1/En-2 double null mutants, but dis appear soon thereafter. Use of an En-1/tau-LacZ knock-in mouse as an autono mous marker for these neurons indicates that they are lost, rather than tha t they change their neurotransmitter phenotype. A single allele of En-1 on an En-2 null background is sufficient to produce a wild type-like substanti a nigra and ventral tegmentum, whereas in contrast a single allele of En-2 on an En-1 null background results in the survival of only a small proporti on of these dopaminergic neurons, a finding that relates to the differentia l expression of En-1 and En-2. Additional findings indicate that En-1 and E n-2 regulate expression of alpha -synuclein, a gene that is genetically lin ked to Parkinson's disease. These findings show that the engrailed genes ar e expressed by midbrain dopaminergic neurons from their generation to adult hood but are not required for their specification. However, the engrailed g enes control the survival of midbrain dopaminergic neurons in a gene dose-d ependent manner. Our findings also suggest a link between engrailed and Par kinson's disease.