Transcriptional control of neuronal migration

点击翻译按钮获取中文摘要

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.**