Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons
| Autor: | Paola Sgadò, Lavinia Alberi, Horst H. Simon |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Programmed cell death
Time Factors Dopamine Oligonucleotides Apoptosis Caspase 3 Substantia nigra Biology Transfection Mice Mice Neurologic Mutants Mesencephalon RNA interference Genetic model Animals Gene Silencing RNA Small Interfering Coloring Agents Molecular Biology Cells Cultured Homeodomain Proteins Neurons Genetics Cell Death Pars compacta Dopaminergic Parkinson Disease Immunohistochemistry engrailed Cell biology Disease Models Animal Bromodeoxyuridine Microscopy Fluorescence nervous system Caspases Mutation RNA Interference Gene Deletion Developmental Biology |
| Zdroj: | Development. 131:3229-3236 |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.01128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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