Department of Cell Biology, Immunology and Neuroscience, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, C/Casanova 143, 08036 Barcelona, Spain.
Neural Dev. 2010 Aug 24;5:21. doi: 10.1186/1749-8104-5-21.
Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.
Here we analyze the role of Nolz1 during LGE development. We show that Nolz1 expression is high in proliferating neural progenitor cells (NPCs) of the LGE subventricular zone. In addition, low levels of Nolz1 are detected in the mantle zone, as well as in the adult striatum. Similarly, Nolz1 is highly expressed in proliferating LGE-derived NPC cultures, but its levels rapidly decrease upon cell differentiation, pointing to a role of Nolz1 in the control of NPC proliferation and/or differentiation. In agreement with this hypothesis, we find that Nolz1 over-expression promotes cell cycle exit of NPCs in neurosphere cultures and negatively regulates proliferation in telencephalic organotypic cultures. Within LGE primary cultures, Nolz1 over-expression promotes the acquisition of a neuronal phenotype, since it increases the number of β-III tubulin (Tuj1)- and microtubule-associated protein (MAP)2-positive neurons, and inhibits astrocyte generation and/or differentiation. Retinoic acid (RA) is one of the most important morphogens involved in striatal neurogenesis, and regulates Nolz1 expression in different systems. Here we show that Nolz1 also responds to this morphogen in E12.5 LGE-derived cell cultures. However, Nolz1 expression is not regulated by RA in E14.5 LGE-derived cell cultures, nor is it affected during LGE development in mouse models that present decreased RA levels. Interestingly, we find that Gsx2, which is necessary for normal RA signaling during LGE development, is also required for Nolz1 expression, which is lost in Gsx2 knockout mice. These findings suggest that Nolz1 might act downstream of Gsx2 to regulate RA-induced neurogenesis. Keeping with this hypothesis, we show that Nolz1 induces the selective expression of the RA receptor (RAR)β without altering RARα or RARγ. In addition, Nozl1 over-expression increases RA signaling since it stimulates the RA response element. This RA signaling is essential for Nolz1-induced neurogenesis, which is impaired in a RA-free environment or in the presence of a RAR inverse agonist. It has been proposed that Drosophila Gsx2 and Nolz1 homologues could cooperate with the transcriptional co-repressors Groucho-TLE to regulate cell proliferation. In agreement with this view, we show that Nolz1 could act in collaboration with TLE-4, as they are expressed at the same time in NPC cultures and during mouse development.
Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.
Nolz1 是一种锌指转录因子，其表达在侧神经节隆起（LGE）中丰富，但它的功能仍然未知。
在这里，我们分析了 Nolz1 在 LGE 发育过程中的作用。我们表明，Nolz1 在 LGE 室下区的增殖神经祖细胞（NPC）中表达较高。此外，在脑膜区以及成年纹状体中检测到低水平的 Nolz1。同样，Nolz1 在增殖的 LGE 衍生 NPC 培养物中高度表达，但在细胞分化后其水平迅速下降，表明 Nolz1 在 NPC 增殖和/或分化的控制中发挥作用。与该假设一致，我们发现 Nolz1 的过表达促进神经球培养物中 NPC 的细胞周期退出，并负调节端脑器官型培养物中的增殖。在 LGE 原代培养物中，Nolz1 的过表达促进神经元表型的获得，因为它增加了 β-III 微管蛋白（Tuj1）和微管相关蛋白（MAP）2 阳性神经元的数量，并抑制星形胶质细胞的产生和/或分化。视黄酸（RA）是参与纹状体神经发生的最重要的形态发生因子之一，并调节不同系统中的 Nolz1 表达。在这里，我们表明 Nolz1 也对 E12.5 LGE 衍生细胞培养物中的这种形态发生因子作出反应。然而，在 E14.5 LGE 衍生的细胞培养物中，Nolz1 的表达不受 RA 调节，也不受在 RA 水平降低的小鼠模型中 LGE 发育过程中的影响。有趣的是，我们发现 Gsx2，它是 LGE 发育过程中正常 RA 信号所必需的，也需要 Nolz1 的表达，在 Gsx2 敲除小鼠中丢失。这些发现表明，Nolz1 可能作为 Gsx2 的下游因子来调节 RA 诱导的神经发生。与该假设一致，我们表明 Nolz1 诱导 RA 受体（RAR）β的选择性表达，而不改变 RARα或 RARγ。此外，Nozl1 的过表达增加了 RA 信号，因为它刺激 RA 反应元件。这种 RA 信号对于 Nolz1 诱导的神经发生是必需的，在没有 RA 的环境中或在存在 RAR 反向激动剂的情况下，这种神经发生会受到损害。已经提出果蝇 Gsx2 和 Nolz1 同源物可以与转录共抑制物 Groucho-TLE 合作来调节细胞增殖。与这一观点一致，我们表明 Nolz1 可以与 TLE-4 合作，因为它们在 NPC 培养物中同时表达，并在小鼠发育过程中表达。
Nolz1 在 LGE 中促进 RA 信号转导，有助于发育过程中的纹状体神经发生。
