Transcriptional control of neuronal migration

哺乳动物大脑皮层的六层结构是由协调的神经元迁移和定位形成的，对神经系统的正确连接至关重要。植物同源域(PhD)-指蛋白6(PHF6)是发育中的大脑中神经元迁移的关键调节因子，然而PHF6驱动神经元正常迁移的潜在分子机制仍未阐明。PhD-Fingers通常存在于与染色质相互作用或在基因转录过程中介导蛋白质-蛋白质相互作用的蛋白质中。重要的是，PHF6在发育中的大脑皮层与RNA聚合酶II相关因子1(PAF1)相互作用，PAF1是转录延长的重要调节因子。在用CHIP-SEQ和RNA-SEQ分析PHF6候选靶基因的全基因组分析中，我发现PHF6占据了发育皮质中的基因体、5‘非翻译区和基因的启动子。最重要的是，我发现PHF6和RNA聚合酶II(POL II)的占据部位有显著重叠。此外，我还发现了与神经元迁移的不同方面有关的蛋白质家族--肾上腺素受体家族的多个成员，作为PHF6的直接转录靶标。此外，我发现PHF6被CDK5磷酸化，CDK5是神经元迁移的重要调节因子，位于Serine199。总而言之，这些发现提出了一些基本问题。PHF6是否与PAF1复合体协同调节哺乳动物大脑中的转录延长，从而驱动神经元迁移？PHF6是否通过诱导不同的Ephin受体基因的表达来调节神经元的迁移和定位？CDK5对PHF6丝氨酸199位的磷酸化是否影响依赖PHF6的大脑皮层神经元迁移？解决这些重要问题将有助于阐明PHF6调节基因表达和促进大脑皮层神经元迁移的分子机制。

The six-layered structure of the mammalian cerebral cortex is formed by coordinated neuronal migration and positioning and is critical to the correct wiring of the nervous system. The plant homeodomain (PHD)-finger protein 6 (PHF6) is a key regulator of neuronal migration in the developing brain, however the underlying molecular mechanisms by which PHF6 drives the proper migration of neurons has remained to be elucidated. The PHD-fingers are commonly found in proteins that either interact with chromatin or mediate protein-protein interactions during gene transcription. Importantly PHF6 interacts with RNA Polymerase II Associated Factor 1 (PAF1), an important regulator of transcriptional elongation, in the developing cerebral cortex. In genome wide analyses of PHF6 candidate target gene by ChIP-Seq and RNA-Seq analyses, I have shown that PHF6 occupies gene bodies, 5’ untranslated (UTR) regions, and promoters of genes in the developing cortex. Most importantly, I found a significant overlap between PHF6 and RNA polymerase II (Pol II) sites of occupancy. In addition, I identified multiple members of the ephrin receptor family, a family of proteins involved in distinct aspects of neuronal migration, as direct transcriptional targets of PHF6. Further, I found that PHF6 is phosphorylated by CDK5, an important regulator of neuronal migration, at Serine199. Together, these findings raise a number of fundamental questions. Does PHF6 co-operate with PAF1 complex to regulate transcriptional elongation in the mammalian brain and thereby drives neuronal migration? Does PHF6 regulate neuronal migration and positioning by inducing the expression of distinct Ephrin receptor genes? Does PHF6 phosphorylation at Serine 199 by CDK5 impact PHF6-dependent neuronal migration in the cerebral cortex? Addressing these important questions will shed light on the molecular mechanism by which PHF6 regulates gene expression and promotes neuronal migration in the cerebral cortex.