Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb
Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb
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DOI：
10.1242/dev.097295
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发表时间：
2014-01-01
期刊：
影响因子：
4.6
通讯作者：
Schulte, Dorothea
中科院分区：
文献类型：
--
作者：
Agoston, Zsuzsa;Heine, Peer;Schulte, Dorothea
Meis同源异型域转录因子控制细胞增殖、细胞命运特化以及发育和疾病中的分化。以前的研究主要集中在Meis对非神经元组织发育的贡献。相比之下，Meis在大脑中的功能还没有得到很好的理解。在这里，我们提供了证据的双重作用的Meis家族蛋白Meis2成人嗅球（OB）神经发生。Meis2强烈表达于脑室下区（SVZ）和吻侧迁移流（RMS）的成神经细胞以及在成人生活中不断替换的一些OB中间神经元中。用表达功能阻断形式的逆转录病毒载体或用小干扰RNA进行的靶向操作表明，Meis活性是细胞自主需要的，用于在体内和体外由SVZ衍生的祖细胞获得一般神经元命运。此外，RMS中的Meis2活性对于OB中多巴胺能肾小球周围神经元的产生是重要的。染色质免疫沉淀鉴定doublecortin和酪氨酸羟化酶作为直接的Meis目标，在新产生的神经元和OB，分别。此外，生化分析揭示了一个以前未被识别的复合物Meis2与Pax6和Dlx2，两个转录因子参与OB神经发生。Pax6在SVZ衍生的神经干细胞和祖细胞中的完全促神经发生活性需要Meis的存在。总的来说，这些结果表明，Meis2与Pax6合作，在成人SVZOB系统中的通用神经发生和多巴胺能命运规范。
Meis homeodomain transcription factors control cell proliferation, cell fate specification and differentiation in development and disease. Previous studies have largely focused on Meis contribution to the development of non-neuronal tissues. By contrast, Meis function in the brain is not well understood. Here, we provide evidence for a dual role of the Meis family protein Meis2 in adult olfactory bulb (OB) neurogenesis. Meis2 is strongly expressed in neuroblasts of the subventricular zone (SVZ) and rostral migratory stream (RMS) and in some of the OB interneurons that are continuously replaced during adult life. Targeted manipulations with retroviral vectors expressing function-blocking forms or with small interfering RNAs demonstrated that Meis activity is cell-autonomously required for the acquisition of a general neuronal fate by SVZ-derived progenitors in vivo and in vitro. Additionally, Meis2 activity in the RMS is important for the generation of dopaminergic periglomerular neurons in the OB. Chromatin immunoprecipitation identified doublecortin and tyrosine hydroxylase as direct Meis targets in newly generated neurons and the OB, respectively. Furthermore, biochemical analyses revealed a previously unrecognized complex of Meis2 with Pax6 and Dlx2, two transcription factors involved in OB neurogenesis. The full pro-neurogenic activity of Pax6 in SVZ derived neural stem and progenitor cells requires the presence of Meis. Collectively, these results show that Meis2 cooperates with Pax6 in generic neurogenesis and dopaminergic fate specification in the adult SVZOB system.