REGULATION OF NEURONAL DEVELOPMENT BY A NOVEL PHF6/PAF1 TRANSCRIPTIONAL PATHWAY

新型 PHF6/PAF1 转录途径调控神经元发育

• 批准号: 8752747
• 负责人: AZAD BONNI
• 金额: $ 33.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752747
• 关键词: Address; Affect; Amino Acids; Animals; Axon; Brain; Cerebral cortex; ChIP-seq; Cognition Disorders; Complex; Data; Dendrites; Development; Eph Family Receptors; Epilepsy; Foundations; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Immigration; Intellectual functioning disability; Lead; Light; Link; Morphology; Mus; Mutation; Neurons; Nuclear; Pathogenesis; Pathway interactions; Patients; Phenocopy; Phenotype; Phosphorylation; Population; Positioning Attribute; Prosencephalon; Proteins; RNA Interference; Receptor Gene; Regulation; Research; Resistance; Role; Serine; Site; Structure; Synapses; Syndrome; Testing; Transcription Elongation; base; developmental disease; genome-wide; in vivo; insight; migration; neuron development; neuronal excitability; novel; novel therapeutic intervention; postnatal; public health relevance; transcriptome sequencing; white matter

DESCRIPTION (provided by applicant): Intellectual disability is a prevalent developmental disorder, affecting 1-3% of the population. Advances in genetics have led to the identification of many intellectual disability proteins. However, how these proteins regulate brain development and the mechanisms by which mutations of these proteins cause intellectual disability remain poorly understood. During the past few years, we have characterized the functions of specific nuclear X-linked intellectual disability (XLID) proteins in brain development. Mutations of the XLID protein PHF6 cause the B¿rjeson-Forssman-Lehmannsyndrome (BFLS), which features intellectual delay and epilepsy. We have discovered that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo. Remarkably, PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. These findings define PHF6 and the PAF1 complex as components of a novel transcriptional pathway that drives neuronal migration in the brain. Our findings have also raised fundamental questions on the mechanisms of the PHF6/PAF1 transcriptional pathway in neuronal migration and on the pathophysiological relevance of this pathway in intellectual disability. To address these questions, we will first perform structure- function analyses of PHF6 in neuronal migration in the mouse cerebral cortex. We will test the effect of BFLS patient-specific mutations of PHF6 on PHF6-dependent transcription and neuronal migration. We will also test the hypothesis that phosphorylation of PHF6 on specific sites regulates PHF6-dependent transcription and neuronal migration. In other studies, we will test the hypothesis that PHF6 regulates transcription elongation of actively transcribed genes in neurons and identify targets of PHF6 that drive neuronal migration. Finally, we will determine the effect of deregulation of the PHF6/PAF1 transcriptional pathway during cortical development on the formation of white matter heterotopias and neuronal excitability in postnatal mice. The proposed research will advance our understanding of the transcriptional mechanisms that govern neuronal positioning in the brain as well as lead to insights into how deregulation of these mechanisms contributes to the pathogenesis of intellectual disability. These studies also hold the potential of laying the foundation for novel therapeutic approaches to the treatment of BFLS and developmental cognitive disorders.

描述（由申请人提供）：智力残疾是一种普遍的发育障碍，影响1-3%的人口。遗传学的进步导致了许多智力残疾蛋白的鉴定。然而，这些蛋白质如何调节大脑发育以及这些蛋白质突变导致智力残疾的机制仍然知之甚少。在过去的几年中，我们已经确定了特定的核X连锁智力残疾（XLID）蛋白在大脑发育中的功能。XLID蛋白PHF 6的突变导致B rjeson-Forssman-Lehmannsyndrome（BFLS），其特征在于智力延迟和癫痫。我们已经发现，敲低PHF 6深刻地损害了小鼠大脑皮层中的神经元迁移在体内。值得注意的是，PHF 6与PAF 1转录延伸复合物物理关联，并且抑制PAF 1表型模仿体内PHF 6敲低诱导的迁移表型。这些发现将PHF 6和PAF 1复合物定义为驱动大脑神经元迁移的新型转录途径的组成部分。我们的研究结果也提出了根本性的问题，PHF 6/PAF 1转录途径在神经元迁移的机制，并在智力残疾的病理生理相关性，这一途径。为了解决这些问题，我们将首先在小鼠大脑皮层神经元迁移中对PHF 6进行结构-功能分析。我们将测试BFLS患者特异性PHF 6突变对PHF 6依赖性转录和神经元迁移的影响。我们还将测试的假设，磷酸化的PHF 6在特定的网站调节PHF 6依赖的转录和神经元迁移。在其他研究中，我们将测试PHF 6调节神经元中活跃转录基因的转录延长的假设，并确定PHF 6驱动神经元迁移的靶点。最后，我们将确定在皮质发育过程中PHF 6/PAF 1转录通路的失调对出生后小鼠白色物质异位和神经元兴奋性形成的影响。拟议的研究将推进我们对控制大脑中神经元定位的转录机制的理解，并深入了解这些机制的失调如何导致智力残疾的发病机制。这些研究也有可能为治疗BFLS和发育性认知障碍的新治疗方法奠定基础。