Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Development. 2014 Jul;141(14):2875-84. doi: 10.1242/dev.105387. Epub 2014 Jun 19.
Progenitor cells are segregated into multiple domains along the dorsoventral axis of the vertebrate neural tube, and each progenitor domain generates particular types of neurons. Selective cross-repressive interactions between pairs of class I and class II transcription factors play important roles in patterning neural progenitors into domains with clear boundaries. Here, we provide evidence that the zinc-finger protein Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary through mutually repressive interactions with the class II protein Nkx2-2. The ventral limit of Sp8 expression is complementary to the dorsal limit of Nkx2-2 expression at the pMN/p3 boundary. Sp8 and Nkx2-2 exert cross-repressive interactions, and changing the expression of Sp8 and Nkx2-2 is coupled with pMN and p3 progenitor fate conversion. Sp8 exerts its neural patterning activities by acting as a transcriptional activator. The expression of a repressive form of Sp8 results in the selective inhibition of motor neuron generation and the ectopic induction of Nkx2-2 expression. Sp8 expression is positively regulated by, but not completely dependent on, Pax6. Furthermore, whereas loss of Pax6 function alone results in disruption of the pMN/p3 domain boundary only in the rostral levels of the spinal cord, loss of both Sp8 and Pax6 functions results in disruption of the pMN/p3 domain boundary along the whole rostrocaudal axis of the spinal cord. We conclude that Sp8 plays a supplementary role to Pax6 in specifying the pMN over p3 progenitor fate through cross-repressive interactions with Nkx2-2.
祖细胞沿着脊椎动物神经管的背腹轴被分隔成多个区域，每个祖细胞区域产生特定类型的神经元。I 类和 II 类转录因子之间的选择性交叉抑制相互作用在将神经祖细胞模式化为具有明确边界的区域方面发挥着重要作用。在这里，我们提供的证据表明，锌指蛋白 Sp8 通过与 II 类蛋白 Nkx2-2 相互抑制作用，在与 Pax6 一起建立 pMN/p3 区域边界方面发挥补充作用。Sp8 表达的腹侧限制与 Nkx2-2 在 pMN/p3 边界处的背侧限制互补。Sp8 和 Nkx2-2 发挥交叉抑制作用，改变 Sp8 和 Nkx2-2 的表达与 pMN 和 p3 祖细胞命运转换相关。Sp8 通过作为转录激活剂发挥其神经模式形成活性。抑制形式的 Sp8 的表达导致运动神经元生成的选择性抑制和 Nkx2-2 表达的异位诱导。Sp8 的表达受到 Pax6 的正向调节，但不完全依赖于 Pax6。此外，尽管单独丧失 Pax6 功能仅导致在脊髓的颅侧水平破坏 pMN/p3 区域边界，但丧失 Sp8 和 Pax6 功能会导致沿整个脊髓的头侧尾侧轴破坏 pMN/p3 区域边界。我们得出结论，Sp8 通过与 Nkx2-2 的交叉抑制相互作用，在与 Pax6 一起指定 pMN 超过 p3 祖细胞命运方面发挥补充作用。
