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Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons.

Author	Lavinia Albéri, Paola Sgadò, Horst H Simon
Citation Information	Development (Cambridge, England), 131:3229-36 (2004)
Keywords	Animals, Apoptosis, Bromodeoxyuridine, Caspase 3, Caspases, Cell Death, Cells, Cultured, Coloring Agents, Disease Models, Animal, Dopamine, Gene Deletion, Gene Silencing, Homeodomain Proteins, Immunohistochemistry, Mesencephalon, Mice, Mice, Neurologic Mutants, Microscopy, Fluorescence, Mutation, Neurons, Oligonucleotides, Parkinson Disease, RNA Interference, RNA, Small Interfering, Time Factors, Transfection
Applications	Immunohistochemistry (tissue)
Related Products	AB152, AB1542
Pub Med ID	15175251

The neuropathological hallmark of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, presumably mediated by apoptosis. The homeobox transcription factors engrailed 1 and engrailed 2 are expressed by this neuronal population from early in development to adulthood. Despite a large mid-hindbrain deletion in double mutants null for both genes, mesencephalic dopaminergic (mDA) neurons are induced, become postmitotic and acquire their neurotransmitter phenotype. However, at birth, no mDA neurons are left. We show that the entire population of these neurons is lost by E14 in the mutant animals, earlier than in any other described genetic model system for Parkinson's disease. This disappearance is caused by apoptosis revealed by the presence of activated caspase 3 in the dying tyrosine hydroxylase-positive mutant cells. Furthermore, using in vitro cell mixing experiments and RNA interference on primary cell culture of ventral midbrain we were able to show that the demise of mDA neurons in the mutant mice is due to a cell-autonomously requirement of the engrailed genes and not a result of the missing mid-hindbrain tissue. Gene silencing in the postmitotic neurons by RNA interference activates caspase 3 and induces apoptosis in less than 24 hours. This rapid induction of cell death in mDA neurons suggests that the engrailed genes participate directly in the regulation of apoptosis, a proposed mechanism for Parkinson's disease.