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首页> 外文期刊>Development >Molecular dissection of Pax6 function: the specific roles of the paired domain and homeodomain in brain development.
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Molecular dissection of Pax6 function: the specific roles of the paired domain and homeodomain in brain development.

机译：Pax6功能的分子解剖：配对结构域和同源结构域在大脑发育中的特定作用。

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摘要

The transcription factor Pax6 plays a key role during development of various organs, including the brain where it affects cell fate, cell proliferation and patterning. To understand how Pax6 coordinates these diverse effects at the molecular level, we examined the role of distinct DNA-binding domains of Pax6, the homeodomain (HD), the paired domain (PD) and its splice variant (5a), using loss- and gain-of-function approaches. Here we show that the PD is necessary for the regulation of neurogenesis, cell proliferation and patterning effects of Pax6, since these aspects are severely affected in the developing forebrain of the Pax6(Aey18) mice with a deletion in the PD but intact homeo- and transactivation domains. In contrast, a mutation of the HD lacking DNA-binding (Pax6(4Neu)) resulted in only subtle defects of forebrain development. We further demonstrate distinct roles of the two splice variants of the PD. Retrovirally mediated overexpression of Pax6 containing exon 5a inhibited cell proliferation without affecting cell fate, while Pax6 containing the canonical form of the PD lacking exon 5a affected simultaneously cell fate and proliferation. These results therefore demonstrate a key role of the PD in brain development and implicate splicing as a pivotal factor regulating the potent neurogenic role of Pax6.
机译：转录因子Pax6在包括大脑在内的各种器官的发育过程中起着关键作用，在大脑中它会影响细胞命运，细胞增殖和模式。为了了解Pax6如何在分子水平上协调这些不同的作用，我们使用了缺失和突变检测了Pax6不同的DNA结合结构域，同源结构域（HD），配对结构域（PD）及其剪接变体（5a）的作用。功能获得方法。在这里，我们显示PD对于调节Pax6的神经发生，细胞增殖和模式作用是必需的，因为这些方面在Pax6（Aey18）小鼠的发育中前脑中受到严重影响，PD缺失但完整的同源和反式激活域。相反，缺乏DNA结合的HD突变（Pax6（4Neu））仅导致前脑发育的细微缺陷。我们进一步证明PD的两个剪接变体的不同作用。含有外显子5a的Pax6的逆转录病毒介导的过表达抑制细胞增殖而不影响细胞命运，而缺乏外显子5a的PD的规范形式的Pax6同时影响细胞的命运和增殖。因此，这些结果证明了PD在大脑发育中的关键作用，并暗示剪接是调节Pax6潜在神经源性作用的关键因素。

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