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Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15242-7. Epub 2006 Oct 2.

Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice.

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  • 1Interdisciplinary Center for Neuroscience, Department of Neuroanatomy, Ruprecht-Karls Universität Heidelberg, 69120 Heidelberg, Germany.


The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1-/-;En2-/-). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1+/-;En2-/-), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.

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