Transcription Factor Control of Neuronal Diversity

神经元多样性的转录因子控制

• 批准号: 10596160
• 负责人: Jane E Johnson
• 金额: $ 49万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596160
• 关键词: ASCL1 gene; Address; Adult; Affect; Alleles; Appearance; BHLH Protein; Behavior; Behavioral; Binding; Binding Sites; Biochemical; Biological Assay; Birth; Cells; Cerebellum; ChIP-seq; Chromatin; Defect; Development; Disease; Dorsal; Ectopic Expression; Embryo; Engineering; Enhancers; Ensure; Enzymes; Epigenetic Process; Equilibrium; Future; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomic Segment; Genomics; Germ Cells; Helix-Turn-Helix Motifs; Human; Hypersensitivity; Knockout Mice; Limb structure; Link; Methyltransferase; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Nervous System; Neural tube; Neurodegenerative Disorders; Neurological Models; Neurons; Nucleic Acid Regulatory Sequences; Pain; Phenotype; Population; Positioning Attribute; Process; Proprioception; Pruritus; Regulator Genes; Reporter; Repression; Retina; Site; Specific qualifier value; Spinal Cord; System; Testing; Touch sensation; Transcription Coactivator; Transcription Repressor; cell type; chromatin modification; excitatory neuron; experimental study; gain of function; gene repression; histone modification; in vivo; inhibitory neuron; loss of function; mutant; nerve stem cell; nervous system disorder; neurodevelopment; neuronal circuitry; progenitor; recruit; regenerative cell; response; somatosensory; stem cell fate; stem cells; tissue regeneration; transcription factor; transcriptome sequencing

Summary The balance between inhibitory and excitatory neurons is established early in development in a process dominated by the interplay between the transcriptional activator PTF1A and the repressor PRDM13 in multiple regions of the nervous system. Initial cell fate decisions that ultimately give rise to inhibitory neurons in the dorsal spinal cord, cerebellum, and retina depend on the early activity of these fate-specifying transcription factors (TFs). PTF1A, like other early- acting basic helix-loop-helix (bHLH) factors, acts as a `master regulator' by triggering downstream genetic cascades. Such TFs have profound effects by restricting progenitor developmental potential long before the appearance of mature neurons. In the absence of PTF1A, neural progenitors fail to generate inhibitory neurons and aberrantly assume an excitatory neuronal fate. Thus, the spatial and temporal control of PTF1A expression controls the formation of the inhibitory/excitatory balance in multiple neuronal circuits. In Aim 1 we will examine the in vivo requirement for a dorsal neural tube specific enhancer for Ptf1a at the molecular, cellular, and behavioral levels. PRDM13, a transcriptional repressor and a direct target of PTF1A, ensures correct specification of dorsal spinal cord inhibitory neurons by repressing genes essential for specifying the alternative excitatory neuronal fates. Because PRDM factors can have methyltransferase activity and/or can recruit other chromatin modifying enzymes, and PRDM13 may bind to bHLH TFs, PRDM13 may provide a molecular link between these factors and accompanying changes in the epigenetic landscape during neuronal subtype- specification. Indeed, PRDM13 binds many similar genomic sites as PTF1A and another bHLH factor ASCL1. In Aims 2 and 3, we will probe PRDM13 functions in the developing nervous system, and test the hypothesis that PRDM13 is recruited to bHLH bound sites to facilitate repressive chromatin modifications to repress transcription through these sites.

总结 抑制性神经元和兴奋性神经元之间的平衡是在发育早期建立的， 这一过程由转录激活因子PTF 1A和转录因子之间的相互作用主导。 在神经系统的多个区域中抑制PRDM 13。最初的细胞命运决定， 最终引起脊髓背侧、小脑和视网膜中的抑制性神经元依赖 对这些指定命运的转录因子（TF）的早期活性的影响。PTF 1A，像其他早期- 作用基本螺旋-环-螺旋（bHLH）因子，通过触发 下游基因级联。这些TF通过限制祖细胞的生长， 在成熟神经元出现之前很久就有发育潜力。在没有 PTF 1A，神经祖细胞不能产生抑制性神经元，并异常地承担 兴奋性神经元的命运因此，PTF 1A表达的空间和时间控制控制了肿瘤的生长。 在多个神经元回路中形成抑制/兴奋平衡。在目标1中， 检查Ptf 1a的背神经管特异性增强子的体内需求， 分子、细胞和行为水平。PRDM 13，一个转录抑制因子和一个直接的 PTF 1A的靶点，通过以下方式确保背侧脊髓抑制性神经元的正确特异性： 抑制基因对于指定替代兴奋性神经元的命运至关重要。因为 PRDM因子可以具有甲基转移酶活性和/或可以募集其他染色质修饰因子。 PRDM 13可以与bHLH TF结合，PRDM 13可以在bHLH TF与bHLH TF之间提供分子连接。 这些因素和伴随的变化，在表观遗传景观在神经元亚型， 规范.事实上，PRDM 13与PTF 1A和另一种bHLH结合许多相似的基因组位点 ASCL 1因子。在目的2和3中，我们将探索PRDM 13在发育中的神经系统中的功能。 系统，并检验PRDM 13被募集到bHLH结合位点以促进 抑制性染色质修饰以抑制通过这些位点的转录。