前神经转录因子的多位点磷酸化调控控制发育和重编程中的增殖与分化。

Neurogenesis (Austin, Tex.) Pub Date : 2015-08-07 eCollection Date: 2015-01-01 DOI:10.1080/23262133.2015.1049733
Anna Philpott
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引用次数: 6

摘要

在神经系统发育过程中,协调增殖和分化过程至关重要。碱性螺旋-环-螺旋转录因子在控制神经元分化和成熟方面发挥着核心作用,也是决定神经元身份的组合密码的组成部分。我们最近已经表明,前神经蛋白Ngn2和Ascl1驱动神经元分化的能力受到细胞周期蛋白依赖性激酶介导的多位点磷酸化的抑制。这限制了下游靶启动子停留时间,从而证明了细胞周期和分化机制之间的直接机制调控联系。前神经蛋白是转录因子混合物的关键成分,可以将人类成纤维细胞直接重编程为神经元。基于我们的观察结果,即磷酸突变的前神经蛋白在体内显示出增强的驱动神经元分化的能力,我们发现在成纤维细胞重编程混合物中用磷酸突变的原神经蛋白取代野生型可显著增强所产生神经元的轴突生长、分支和电生理成熟度。这里提出了一个模型,可以解释去磷酸化的前神经蛋白驱动神经元分化的能力增强,并强调了这一新兴领域中一些尚未回答的问题。
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Multi-site phospho-regulation of proneural transcription factors controls proliferation versus differentiation in development and reprogramming.

During development of the nervous system, it is essential to co-ordinate the processes of proliferation and differentiation. Basic helix-loop-helix transcription factors play a central role in controlling neuronal differentiation and maturation as well as being components of the combinatorial code that determines neuronal identity. We have recently shown that the ability of the proneural proteins Ngn2 and Ascl1 to drive neuronal differentiation is inhibited by cyclin dependent kinase-mediated multi-site phosphorylation. This limits downstream target promoter dwell time, thus demonstrating a direct mechanistic regulatory link between the cell cycle and differentiation machinery.Proneural proteins are key components of transcription factor cocktails that can bring about the direct reprogramming of human fibroblasts into neurons. Building on our observations demonstrating that phospho-mutant proneural proteins show an enhanced ability to drive neuronal differentiation in vivo, we see that replacing wild-type with phospho-mutant proneural proteins in fibroblast reprogramming cocktails significantly enhances the axonal outgrowth, branching and electrophysiological maturity of the neurons generated. A model is presented here that can explain the enhanced ability of dephosphorylated proneural proteins to drive neuronal differentiation, and some unanswered questions in this emerging area are highlighted.

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