Specification of hypothalamic neurons by dual regulation of the homeodomain protein Orthopedia
Specification of hypothalamic neurons by dual regulation of the homeodomain protein Orthopedia
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DOI：
10.1242/dev.011262
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发表时间：
2007-12-15
期刊：
影响因子：
4.6
通讯作者：
Levkowitz, Gil
中科院分区：
文献类型：
--
作者：
Blechman, Janna;Borodovsky, Nataliya;Levkowitz, Gil
在发育中的下丘脑中，各种神经元以高度协调但知之甚少的过程彼此相邻地产生。一个关键的问题，仍然没有答案的是如何协调发展的多种神经元类型是在这个相对狭窄的解剖区域实现。我们专注于多巴胺（DA）和催产素（OT）神经元作为两个突出的下丘脑细胞类型的发展的范例。我们报告说，在斑马鱼DA和OT样神经元的发展是精心策划的两个新的途径，调节表达的同源结构域的蛋白质Orthopedia（OTP），下丘脑神经分化的关键决定因素。遗传分析表明，G蛋白偶联受体PAC1和含锌指的转录因子Fezl作用于Otp的上游。体内和体外实验表明，Fezl和PAC 1分别在转录和转录后水平调节Otp。我们的数据揭示了一个新的遗传网络控制脊椎动物下丘脑神经元的规范，并将OTP作为Fezl和PAC 1介导的分化的关键决定因素。
In the developing hypothalamus, a variety of neurons are generated adjacent to each other in a highly coordinated, but poorly understood process. A critical question that remains unanswered is how coordinated development of multiple neuronal types is achieved in this relatively narrow anatomical region. We focus on dopaminergic (DA) and oxytocinergic (OT) neurons as a paradigm for development of two prominent hypothalamic cell types. We report that the development of DA and OT-like neurons in the zebrafish is orchestrated by two novel pathways that regulate the expression of the homeodomain-containing protein Orthopedia (Otp), a key determinant of hypothalamic neural differentiation. Genetic analysis showed that the G-protein-coupled receptor PAC1 and the zinc finger-containing transcription factor Fezl act upstream to Otp. In vivo and in vitro experiments demonstrated that Fezl and PAC1 regulate Otp at the transcriptional and the post-transcriptional levels, respectively. Our data reveal a new genetic network controlling the specification of hypothalamic neurons in vertebrates, and places Otp as a critical determinant underlying Fezl- and PAC1-mediated differentiation.