Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons
Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons
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DOI：
10.1242/dev.01128
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发表时间：
2004-07-01
期刊：
影响因子：
4.6
通讯作者：
Simon, HH
中科院分区：
文献类型：
--
作者：
Albéri, L;Sgadó, P;Simon, HH
帕金森病的神经病理学标志是黑质丘脑部多巴胺能神经元的丢失，推测是由细胞凋亡介导的。同源异型盒转录因子enrailed 1和enrailed 2由该神经元群体从发育早期到成年期表达。尽管一个大的中后脑缺失双突变体无效的两个基因，中脑多巴胺能（mDA）神经元诱导，成为有丝分裂后，并获得其神经递质表型。然而，在出生时，没有mDA神经元留下。我们表明，这些神经元的整个人口是E14在突变动物中丢失，早于任何其他描述的帕金森病遗传模型系统。这种消失是由凋亡引起的，凋亡是由在垂死的酪氨酸羟化酶阳性突变细胞中存在活化的半胱天冬酶3所揭示的。此外，使用体外细胞混合实验和RNA干扰腹侧中脑的原代细胞培养，我们能够表明，mDA神经元在突变小鼠的死亡是由于细胞自主要求的enrailed基因，而不是一个丢失的中后脑组织的结果。通过RNA干扰在有丝分裂后神经元中的基因沉默在不到24小时内激活半胱天冬酶3并诱导凋亡。这种在mDA神经元中快速诱导细胞死亡的现象表明，植入的基因直接参与了细胞凋亡的调节，这是帕金森病的一种拟议机制。
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.