Foxp-regulated signaling pathways in brain development

大脑发育中 Foxp 调节的信号通路

基本信息

批准号：
10630270
负责人：
Genevieve Konopka
金额：
$ 57.81万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630270
关键词：
Acute Affect Anatomy Automobile Driving Behavior Behavioral Biological Assay Brain Brain Diseases Bromodeoxyuridine Cell physiology Cells Childhood Compensation Corpus striatum structure Data Development Disease Dopamine Receptor Electrophysiology (science)Electroporation Embryo Loss Etiology FOXP1 gene FOXP2 gene Family Gene Expression Genes Genetic Transcription Goals Heritability Individual Injections Intellectual functioning disability Interneurons Knockout Mice Laboratories Language Disorders Link Measurement Molecular Mutation Neocortex Neuroanatomy Neurodevelopmental Disorder Neurons Normal Cell Ontology Pathway interactions Phenotype Physiology Proliferating Proteins Publications Publishing RNA analysis Recurrence Reversal Learning Risk Rodent Model Role Signal Pathway Signal Transduction Slice Specific qualifier value Speech Synaptic Transmission Tamoxifen Technology Testing Thick Time Tissue Harvesting Variant Work autism spectrum disorder behavioral phenotyping cell type conditional knockout de novo mutation developmental disease experimental study functional genomics functional outcomes genomic data in utero insight member migration neocortical neuronal excitability neuropsychiatric disorder postnatal progenitor programs risk variant single nucleus RNA-sequencing single-cell RNA sequencing social synaptic function targeted treatment transcription factor transcriptome sequencing

项目摘要

Project Summary/Abstract The contribution of individual disease-relevant genes to brain development still remains unknown. The long-term goal of our laboratory is to elucidate the intersection of molecular signaling pathways that are disrupted in neurodevelopmental disorders with those pathways that are important for specific aspects of brain development. Two members of the FOXP family of transcription factors, FOXP1 and FOXP2, have been linked to monogenetic forms of intellectual disability, autism spectrum disorders, and specific speech and language deficits. Variants in FOXP1 or FOXP2 are among the most significant genes associated with autism spectrum disorders. We previously showed that Foxp1 and Foxp2 both have significant contributions to cortical and striatal development. We linked these developmental changes via studies of gene expression, electrophysiology, and behaviors. We further identified non-cell-autonomous changes in gene expression using newly available single-cell RNA- sequencing technology. Based on these data, the central hypothesis driving this proposal is that Foxp1 and Foxp2 are key orchestrators of transcriptional signaling cascades in a cell type-specific manner that are important for neuronal function and are at risk in neurodevelopmental disorders such as autism. We propose to identify these cell type-specific contributions in the developing cortex by using rodent models through three specific aims: 1) Determine the cell type-specific gene expression programs regulated by Foxp1 in the developing cortex; 2) Determine the cell type-specific gene expression programs regulated by Foxp2 in the developing cortex; and 3) Assess the role of Foxp1 and Foxp2 in cell type-specific activity-dependent neuronal function. Together, these aims will delineate the cell type contribution of both Foxp1 and Foxp2 to cortical development. The rodent models and cell-type specific genomic datasets will aprovide insight into the basic molecular mechanisms governing normal mammalian brain development.

项目概要/摘要个体疾病相关基因对大脑发育的贡献仍然未知。长期来看我们实验室的目标是阐明被破坏的分子信号传导途径的交叉点神经发育障碍，其通路对大脑发育的特定方面很重要。 FOXP 转录因子家族的两个成员 FOXP1 和 FOXP2 与单基因遗传有关各种形式的智力障碍、自闭症谱系障碍以及特定的言语和语言缺陷。变种 FOXP1 或 FOXP2 是与自闭症谱系障碍相关的最重要的基因之一。我们先前表明 Foxp1 和 Foxp2 对皮质和纹状体的发育都有重要贡献。我们通过基因表达、电生理学和行为的研究将这些发育变化联系起来。我们使用新可用的单细胞 RNA 进一步鉴定了基因表达的非细胞自主变化测序技术。基于这些数据，推动该提议的中心假设是 Foxp1 和 Foxp2 是以细胞类型特异性方式转录信号级联的关键协调器，对神经元功能很重要，并且存在自闭症等神经发育障碍的风险。我们提议通过使用啮齿动物模型来识别发育中皮层中这些细胞类型特异性的贡献三个具体目标：1）确定Foxp1在细胞中调控的细胞类型特异性基因表达程序皮质发育； 2)确定Foxp2在细胞中调控的细胞类型特异性基因表达程序皮质发育； 3) 评估 Foxp1 和 Foxp2 在细胞类型特异性活性依赖性神经元中的作用功能。总之，这些目标将描述 Foxp1 和 Foxp2 对皮质的细胞类型贡献发展。啮齿动物模型和细胞类型特定基因组数据集将提供对基本知识的深入了解控制正常哺乳动物大脑发育的分子机制。