Transcription Factor Control of Neuronal Diversity

神经元多样性的转录因子控制

基本信息

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
项目类别：
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

项目摘要

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.

概括抑制性和兴奋性神经元之间的平衡是在发育早期建立的过程以转录激活剂PTF1A和神经系统多个区域的阻遏物PRDM13。最初的细胞命运决定最终会引起背脊髓，小脑和视网膜的抑制性神经元关于这些命运指定转录因子（TFS）的早期活性。 PTF1A，像其他早期代理基本的螺旋 - 环螺旋（BHLH）因素，通过触发起作用的“主调节器” 下游遗传级联。这样的TF通过限制祖细胞具有深远的影响发育潜力早在成熟神经元出现之前。在没有 PTF1A，神经祖细胞无法产生抑制性神经元，异常假设兴奋性神经元命运。因此，PTF1A表达的空间和时间控制控制多个神经元电路中抑制/兴奋性平衡的形成。在目标1中，我们将检查体内对ptf1a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。 PRDM13，转录阻遏物和直接 PTF1A的靶标，确保正确规范背脊髓抑制神经元抑制基因对于指定替代性兴奋性神经元命运必不可少的基因。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酶和PRDM13可能与BHLH TFS结合，PRDM13可能会在这些因素以及神经元亚型期间表观遗传景观的变化规格。实际上，PRDM13结合了许多类似的基因组位点，与PTF1A和另一个BHLH结合因子ASCL1。在目标2和3中，我们将在发育中的紧张中探测PRDM13的功能系统，并检验了PRDM13被招募到BHLH绑定站点以促进的假设抑制染色质修饰以通过这些位点抑制转录。