Pbx1 is required for adult subventricular zone neurogenesis
Pbx1 is required for adult subventricular zone neurogenesis
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DOI：
10.1242/dev.128033
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发表时间：
2016-07-01
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：
Grebbin, Britta Moyo;Hau, Ann-Christin;Schulte, Dorothea
TALE同源结构域蛋白作为异聚复合物的组分起作用，所述异聚复合物含有PBC和MEIS/PREP亚类中的每一个成员。我们最近发现MEIS 2与神经源性转录因子PAX 6在啮齿类动物成年脑室下区（SVZ）神经发生的控制中合作。PBC蛋白PBX 1在SVZ中的表达已有报道，但其功能作用尚未研究。使用遗传功能丧失小鼠模型，我们现在表明Pbx 1是SVZ神经发生的早期调节因子。通过逆转录病毒转导Cre重组酶，靶向缺失Pbx 1，使其进入携带Pbx 1 floxed等位基因的Pbx 2缺陷型SVZ干细胞和祖细胞，显著减少了神经元的产生，增加了少突胶质细胞的产生。相比之下，在Pbx 2空白背景下，在吻侧迁移流中，Pbx 1在神经元定向成神经细胞中的表达缺失，严重损害了细胞存活。通过内源性组织或分离细胞的染色质免疫沉淀，我们进一步检测到PBX 1结合到已知的神经元特异性基因Dcx和Th的调控区，这些基因在SVZ神经发生的正常程序中表达前几天甚至几周，这表明PBX 1可能作为一个引发因子来标记这些基因以进行随后的激活。总的来说，我们的研究结果表明，PBX 1调节成人神经细胞的命运决定的方式超出了它的异源二聚化伙伴MEIS 2。
TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2.