Fate of Midbrain Dopaminergic Neurons Controlled by the Engrailed Genes

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Abstract
Deficiencies in neurotransmitter-specific cell groups in the midbrain result in prominent neural disorders, including Parkinson's disease, which is caused by the loss of dopaminergic neurons of the substantia nigra. We have investigated in mice the role of the engrailed homeodomain transcription factors, En-1 and En-2, in controlling the developmental fate of midbrain dopaminergic neurons.En-1is highly expressed by essentially all dopaminergic neurons in the substantia nigra and ventral tegmentum, whereasEn-2is highly expressed by a subset of them. These neurons are generated and differentiate their dopaminergic phenotype inEn-1/En-2double null mutants, but disappear soon thereafter. Use of anEn-1/tau-LacZknock-in mouse as an autonomous marker for these neurons indicates that they are lost, rather than that they change their neurotransmitter phenotype. A single allele ofEn-1on anEn-2null background is sufficient to produce a wild type-like substantia nigra and ventral tegmentum, whereas in contrast a single allele ofEn-2on anEn-1null background results in the survival of only a small proportion of these dopaminergic neurons, a finding that relates to the differential expression ofEn-1andEn-2. Additional findings indicate that En-1 and En-2 regulate expression of α-synuclein, a gene that is genetically linked to Parkinson's disease. These findings show that the engrailed genes are expressed by midbrain dopaminergic neurons from their generation to adulthood but are not required for their specification. However, the engrailed genes control the survival of midbrain dopaminergic neurons in a gene dose-dependent manner. Our findings also suggest a link between engrailed and Parkinson's disease.