Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP
Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP
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DOI：
10.1038/nn.2661
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发表时间：
2010-12-01
影响因子：
25
通讯作者：
Simeone, Antonio
中科院分区：
文献类型：
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作者：
Di Salvio, Michela;Di Giovannantonio, Luca Giovanni;Simeone, Antonio
中脑-间脑多巴胺能神经元控制运动活动和情绪，并在神经退行性疾病和精神疾病中受到影响。同源异型蛋白Otx 2仅限于腹侧被盖区（VTA）神经元，这些神经元与表达Girk 2和多巴胺转运蛋白（Dat）的糖基化活性形式的神经元预先互补。高水平的糖基化Dat标记神经元，具有有效的多巴胺摄取和明显的帕金森变性的脆弱性。我们发现Otx 2通过拮抗背外侧VTA的分子和功能特征（如Girk 2和Dat表达）来控制神经元亚型身份。Otx 2限制了腹侧被盖区神经元的数量，有效地摄取多巴胺，并赋予1-甲基-4-苯基-1，2，3，6-四氢吡啶-盐酸（MPTP）神经毒素的抗性。Otx 2的异位表达也提供了有效的神经保护MPTP的黑质神经元。这些研究结果表明，Otx 2是指定腹侧被盖区神经元亚型身份所必需的，并可能拮抗帕金森毒素MPTP的脆弱性。
Mesencephalic-diencephalic dopaminergic neurons control locomotor activity and emotion and are affected in neurodegenerative and psychiatric diseases. The homeoprotein Otx2 is restricted to ventral tegmental area (VTA) neurons that are prevalently complementary to those expressing Girk2 and glycosylated active form of the dopamine transporter (Dat). High levels of glycosylated Dat mark neurons with efficient dopamine uptake and pronounced vulnerability to Parkinsonian degeneration. We found that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of dorsal-lateral VTA, such as Girk2 and Dat expression. Otx2 limited the number of VTA neurons with efficient dopamine uptake and conferred resistance to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCI (MPTP) neurotoxin. Ectopic Otx2 expression also provided neurons of the substantia nigra with efficient neuroprotection to MPTP. These findings indicate that Otx2 is required to specify neuron subtype identity in VTA and may antagonize vulnerability to the Parkinsonian toxin MPTP.